Use of SOS1 inhibitors and amivantamab to treat cancer

Abstract

The present disclosure provides compounds and pharmaceutically acceptable salt thereof, and methods of using the same. The compounds and methods have a range of utilities as therapeutics, diagnostics, and research tools. In particular, the subject compositions and methods are useful for reducing signaling output of oncogenic proteins when used in combination with one or more other therapeutic agents.

Description

[0001] METHODS OF MODULATING CELL PROLIFERATION

[0002] CROSS-REFERENCE

[0003]

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 593,224, filed October 25, 2023 and U.S. Provisional Application No. 63 / 572,117, filed March 29, 2024, each incorporated herein by reference in its entirety.

[0004] SEQUENCE LISTING

[0005]

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on October 22, 2024, is named 56690_776_601_SL.xml and is 4,097 bytes in size.

[0006] BACKGROUND

[0007]

[0003] The ErbB family of receptor tyrosine kinases includes EGFR (HERl / ErbBl), EIER2 (ErbB2), EIER3 (ErbB3) and HER4 (ErbB4), each of which is a mediator of normal cell growth and development. In particular, phosphorylation of EGFR activates downstream signaling pathways — including the PI3K / AKT / mTOR, STAT, and RAS / MAPK pathways — that involve cell proliferation, angiogenesis, apoptosis, and metastasis. Overexpression of EGFR is frequently observed in a variety of tumors, including brain, breast, cervical, colorectal, esophageal, head and neck, kidney, lung, ovarian, and stomach cancers.

[0008]

[0004] EGFR mutations have been detected in over 40% of non-small cell lung cancer (NSCLC) cases in Asia and over 10% of NSCLC cases in North America and Europe, making them the most prevalent genetic alterations in NSCLC. The L858R point mutation and exon 19 deletions are often referred to as classical EGFR activating mutations and result in constitutive activation of EGFR and downstream signaling pathways, particularly in non- small cell lung cancer (NSCLC). These mutants have a greater affinity for ATP-competitive EGFR inhibitors, which, combined with the increased reliance of the tumor cells on EGFR signaling, creates a large therapeutic window for EGFR inhibition, making it an effective treatment for NSCLC patients with classical EGFR mutations. However, certain exon 20 mutations, including T790M and exon 20 insertions, activate EGFR while affording the tumor resistance to first- and second-generation EGFR inhibitors targeting the classical EGFR mutations, such as gefitinib, erlotinib, and afatinib. Lung cancer is the leading cause of cancer-related death worldwide, due in part to these resistance mechanisms. In 2023, an estimated 238,000 people will be diagnosed with lung and bronchus cancer and approximately 127,000 people will die from lung and bronchus cancer in the United States.

[0009]

[0005] Son of Sevenless 1 (SOS1), a homolog of SOS2 in mammalian cells, acts as a guanine nucleotide exchange factor (GEF) that promotes release of inactive GDP from RAS-family proteins to enable GTP binding. SOS1 has been implicated in cancer via its ability to activate RAS-family protein signaling. SOS1 interacts with the adaptor protein Grb2 and the resulting SOSl / Grb2 complex binds to activated / phosphorylated Receptor Tyrosine Kinases (e.g., EGFR, ErbB2, ErbB 3, ErbB4,TrkA, TrkB, TrkC, RET, c-MET, VEGFR 1 / 2 / 3). SOS1 is also recruited to other phosphorylated cell surface receptors such as the T cell Receptor (TCR), B cell Receptor (BCR) and monocyte colony-stimulating factor receptor. This localization of SOS1 to the plasma membrane, proximal to RAS-family proteins, enables SOS1 to promote RAS-family protein activation. SOS 1 -activation of RAS-family proteins can also be mediated by the interaction of SOSl / Grb2 with the BCR-ABL oncoprotein commonly found in chronic myelogenous leukemia. SUMMARY

[0010]

[0006] There exists a considerable need for identifying relevant monotherapy as well as combination therapy to address the long-felt need for gaining sustained therapeutic benefit against EGFR-mediated diseases, including various types of cancer. The present invention addresses these needs and provides related advantages as well.

[0007] In certain aspects, the present disclosure provides a method of treating an EGFR-mediated cancer in a subject, comprising administering to the subject (a) a SOS1 inhibitor and (b) amivantamab, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b). In some embodiments, the cancer is lung cancer, such as non-small cell lung cancer. In some embodiments, cancer cells of the subject comprise an EGFR mutation. In some embodiments, the EGFR mutation is selected from an L858R mutation, an exon 19 deletion, and an exon 20 insertion. In some embodiments, the EGFR mutation is an exon 20 insertion. In some embodiments, the subject exhibits relapse of the cancer. In some embodiments, the subject has previously been treated with chemotherapy. In some embodiments, the subject has previously been treated with platinum-based chemotherapy. In some embodiments, the subject has previously been treated with a tyrosine kinase inhibitor (TKI) against EGFR prior to administering (a) and (b). In some embodiments, the subject has previously been treated with a non-exon 20 insertion EGFR TKI, such as a non-exon 20 insertion EGFR TKI selected from gefitinib, erlotinib, afatinib, lazertinib, osimertinib, dacomitinib, neratinib, cetuximab, panitumumab, lapatinib, necitumumab, nazartinib, vandetanib, BLU-945, and zorifertinib. In some embodiments, the subject has previously been treated with an EGFR exon 20 insertion TKI, such as an EGFR exon 20 insertion TKI selected from poziotinib, mobocertinib, amivantamab, zipalertinib, sunvozertinib, BAY-2927088, BLU-451, and STX-721. In some embodiments, the subject exhibits resistance or intolerance to the TKI. In some embodiments, the subject exhibits resistance or intolerance to osimertinib. In some embodiments, resistance to the TKI is characterized by one or more changes selected from (1) progression of the cancer, (2) EGFR gene mutation, (3) loss of EGFR T790M mutation, (4) EGFR gene amplification, (5) MET amplification, (6) HER2 amplification, (7) RAS-MAPK pathway activation, (8) PI3K pathway activation, (9) cell-cycle gene alteration, (10) oncogenic fusion, (11) histologic transformation, and (12) phenotypic transformation.

[0011]

[0008] In certain aspects, the present disclosure provides a method of reducing proliferation of cancer cells comprising an epidermal growth factor receptor (EGFR) exon 20 insertion, the method comprising administering to the cells (a) a SOS1 inhibitor and (b) amivantamab, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b). In some embodiments, the cancer cells are non-small cell lung cancer cells. In some embodiments, the administration of (a) and (b) synergistically reduces proliferation of the cancer cells with a synergistic value of at least 0. 1 as ascertained by Bliss independence criterion. In some embodiments, the synergistic value is ascertained by Bliss independence criterion in accordance with the formula: YAB.O - YAB.P, wherein: YAB.O is observed percent growth inhibition of the cancer cells by the application of (a) and (b) comprising (a) at dose A and (b) at dose B: YAB.P is predicted percent growth inhibition of the cancer cells by the application of (a) and (b) comprising (a) at dose A and (b) at dose B, wherein YAB.P = YA + YB - Y \Yi;: YA is observed percent growth inhibition of the cancer cells by (a) alone at dose A; YB is observed percent growth inhibition of the cancer cells by (b) alone at dose B: and YAYB is the product of YA and YB. In some embodiments, the synergistic value is at least 0.4, such as at least 1 or at least 5.

[0012]

[0009] In certain aspects, the present disclosure provides a method of downregulating EGFR signaling output in a plurality of non-small cell lung cancer cells, comprising: (i) assessing EGFR mutation status in a biological sample comprising nucleic acid from the subject; and (ii) administering an effective dose of (a) a SOS1 inhibitor and an effective dose of (b) amivantamab if an EGFR exon 20 insertion is detected in the sample, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b).

[0013]

[0010] In practicing any of the subject methods, the cancer cells may previously have been treated with chemotherapy, such as platinum-based chemotherapy. In some embodiments, the cancer cells have previously been treated with a tyrosine kinase inhibitor (TKI) against EGFR other than amivantamab prior to administering (a). In some embodiments, the cancer cells have previously been treated with a non-exon 20 insertion EGFR TKI, such as a non-exon 20 insertion EGFR TKI selected from gefitinib, erlotinib, afatinib, lazertinib, osimertinib, dacomitinib, neratinib, cetuximab, panitumumab, lapatinib, necitumumab, nazartinib, vandetanib, BLU-945, and zorifertinib. In some embodiments, the subject has previously been treated with an EGFR exon 20 insertion TKI, such as an EGFR exon 20 insertion TKI selected from poziotinib, mobocertinib, zipalertinib, sunvozertinib, BAY-2927088, BLU-451, and STX-721. In some embodiments, the cancer cells exhibit resistance or intolerance to the TKI. In some embodiments, resistance to the TKI is characterized by one or more changes selected from (1) progression of the cancer, (2) EGFR gene mutation, (3) loss of EGFR T790M mutation, (4) EGFR gene amplification, {S') MET amplification, (6) HER2 amplification, (7) RAS-MAPK pathway activation, (8) PI3K pathway activation, (9) cellcycle gene alteration, (10) oncogenic fusion, (11) histologic transformation, and (12) phenotypic transformation.

[0014] [OH] A method described herein may further comprise administering (c) an additional agent or additional therapy. In some embodiments, the additional agent is selected from an EGFR TKI other than amivantamab, a MET inhibitor, an immunomodulatory agent, an anti-nausea agent, an antiemetic, a pain reliever, and a chemotherapeutic agent. In some embodiments, the additional agent is selected from an immunomodulatory agent, a cytokine blockade agent, and a checkpoint immune blockade agent. In some embodiments, the additional agent is selected from an anti-PD-Ll antibody, an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-LAG3 antibody, an anti-TIM3 antibody, and combinations thereof. In some embodiments, the additional therapy is selected from surgery, cell therapy, chemotherapy, and radiation.

[0015]

[0012] In practicing any of the subject methods, the administration of (a) and (b) may reduce incidence of one or more adverse event associated with amivantamab, such as an adverse event selected from rash, pruritus, dry skin, fatigue, edema, pyrexia, paronychia, pneumonia, musculoskeletal pain, dyspnea, cough, nausea, stomatitis, constipation, vomiting, diarrhea, abdominal pain, hemorrhage, decreased appetite, peripheral neuropathy, dizziness, and headache. In some embodiments, the adverse event is selected from diarrhea, rash, and nausea. In some embodiments, the administration of (a) and (b) exhibits a synergistic effect. In some embodiments, the synergistic effect is characterized by a synergistic value of at least 0.05 as ascertained by Bliss independence criterion. In some embodiments, one or both of (a) and (b) are administered at a sub-therapeutic dose but achieve a therapeutic effect at least comparable to administering (a) or (b) alone at its therapeutically effective amount. In some embodiments, amivantamab is administered at a dose less than about 25% the standard monotherapy dose. In some embodiments, (a) and (b) are administered in the same formulation. In some embodiments, (a) and (b) are administered in separate formulations.

[0016]

[0013] In practicing any of the subject methods, the S0S1 inhibitor may be selected from BI-3406, MRTX0902, BAY 293, RMC-5845, and BI-1701963. In some embodiments, the S0S1 inhibitor is a compound of Formula (1-1):

[0017] or a pharmaceutically acceptable salt or solvate thereof, wherein: is selected from C5.7 carbocycle and 5- to 7-membered heterocycle, each of which is optionally substituted with one or more R11; is absent or selected from C3.8 carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more Rl la;

[0018] L1is selected from a bond, Ci-6 alkylene, and Ci-6 haloalkylene:

[0019] L2is selected from C5.25 alkylene, C5.25 alkenylene, C5.25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is optionally substituted with one or more Rl lb, wherein L2is covalently bound to one of W3, W4, W5, W6, or W7;

[0020] W3is selected from N(R3b), N, C(R3), and C(O);

[0021] W4is selected from N(R4b), N, C(R4), and C(O);

[0022] W5is selected from N(R5b), N, and C(R5);

[0023] W6is selected from C(R6) and C(O);

[0024] W7is C(R7);

[0025] R1is C1.3 alkyl optionally substituted with one or more Rllc;

[0026] R8is selected from hydrogen, halogen, -CN, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10- membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), - N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), - N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), - CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein each Ci.6alkyl, C2.6alkenyl, C2.6alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20;

[0027] R3, R4, R5, R6, and R7are each independently selected from a bond to L2, hydrogen, halogen, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), - C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20; R3b, R4b, and R5bare each independently selected from a bond to L2, hydrogen, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -C(O)OR12, - OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, - S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20;

[0028] R11and Rllaare each independently selected at each occurrence from halogen, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), -CH2N(R12)S(O)2(R13), and - P(O)(R17)(R17a), wherein Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20;

[0029] Rllbis independently selected at each occurrence from halogen, oxo, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), -CH2N(R12)S(O)2(R13), and - P(O)(R17)(R17a), wherein Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20;

[0030] Rllcis independently selected at each occurrence from halogen, -OR12, and -N(R12)(R13);

[0031] R12is independently selected at each occurrence from hydrogen, Ci-6 alkyl, Ci-e haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20;

[0032] R13is independently selected at each occurrence from hydrogen, Ci-6 alkyl, and Ci-6 haloalkyl; or R12and R13, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycle optionally substituted with one, two, or three R20;

[0033] R14is independently selected at each occurrence from hydrogen, Ci-6 alkyl, and Ci-6 haloalkyl;

[0034] R15is independently selected at each occurrence from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20;

[0035] R17and R17aare each independently selected at each occurrence from Ci-6 alkyl and C3.6 cycloalkyl, wherein Ci-6 alkyl and C3.6 cycloalkyl are optionally substituted with one, two or three R20; or R17and R17a, together with the phosphorous atom to which they are attached, form a 3- to 10-membered heterocycle;

[0036] R20is independently selected at each occurrence from halogen, oxo, =NH, -CN, Ci-6 alkyl, C2-6 alkenyl, C2- e alkynyl, C3-10 carbocycle, -CH2-(C3-IO carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, - S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, -CH2-(C3-IO carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci.6alkoxy, Ci.6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, - N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25;

[0037] R21is independently selected at each occurrence from H, Ci-6 alkyl, Ci-6 haloalkyl, C2.e alkenyl, C2.e alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and Ci-6 alkyl;

[0038] R22is independently selected at each occurrence from H, Ci-6 alkyl, Ci-6 haloalkyl, C2.e alkenyl, C2.e alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and Ci-6 alkyl;

[0039] R23is independently selected at each occurrence from H and Ci-e alkyl;

[0040] R24is independently selected at each occurrence from H and Ci-e alkyl;

[0041] R25is independently selected at each occurrence from Ci-6 alkyl, C2.e alkenyl, C2.e alkynyl, carbocycle, and 3- to 10-membered heterocycle, wherein Ci-6 alkyl, carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, Ci-e alkyl, Ci-e haloalkyl, Ci-6 alkoxy, C3-10 carbocycle, and 3- to 10-membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0042]

[0014] In certain aspects, the present disclosure provides a kit for use in reducing proliferation of cancer cells comprising an epidermal growth factor receptor (EGFR) exon 20 insertion, the kit comprising: (1) a composition comprising a SOS1 inhibitor of Formula (1-1); (2) a composition comprising amivantamab; and (3) instructions for using the composition(s) of (1) and (2). In some embodiments, the SOS1 inhibitor and the amivantamab are formulated in a same unit dosage form. In some embodiments, the SOS1 inhibitor and the amivantamab are formulated in different unit dosage forms.

[0043]

[0015] In certain aspects, the present disclosure provides a pharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (1-1), or a pharmaceutically acceptable salt or solvate thereof, (ii) amivantamab, and (iii) a pharmaceutically acceptable excipient. In certain aspects, the present disclosure provides a method of treating an EGFR-mediated cancer in a subject, comprising administering to the subject a pharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (1-1), or a pharmaceutically acceptable salt or solvate thereof, (ii) amivantamab, and (iii) a pharmaceutically acceptable excipient. In practicing any of the subject methods, the subject may be a naive subject that has not been treated with a TKI against EGFR prior to administering (a) and (b).

[0044] INCORPORATION BY REFERENCE

[0045]

[0016] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0046] BRIEF DESCRIPTION OF DRAWINGS

[0047]

[0017] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:

[0018] FIG. 1 shows results of a study in which mice bearing Ba / F3-EGFR Exon 20 insertion (V769_D770insASV) allograft tumors were treated with (i) a SOS1 inhibitor of the present disclosure (e.g., Compound A) alone, (ii) amivantamab alone, or (iii) a combination of (i) and (ii). The results demonstrate that the SOS1 inhibitor disclosed herein synergistically inhibits tumor growth in combination with amivantamab.

[0048]

[0019] FIG. 2 shows results of a study in which LU0858 mice (an NSCLC patient-derived xenograft (PDX) model exhibiting EGFR-L858R mutation with amplified MET) were treated with (i) a SOS1 inhibitor of the present disclosure (e.g., Compound A) alone, (ii) amivantamab alone, or (iii) a combination of (i) and (ii). The results demonstrate that the SOS1 inhibitor disclosed herein in combination with amivantamab synergistically reduces tumor volume in EGFR-mediated lung cancer, particularly MET amplified lung cancer.

[0049]

[0020] FIG. 3 shows results of a study in which mice bearing a squamous NSCLC PDX model exhibiting an EGFR-Exon 20 D772_N773insDNP mutation were treated with (i) a SOS1 inhibitor of the present disclosure (e.g., Compound A) alone, (ii) amivantamab alone, or (iii) a combination of (i) and (ii). The results demonstrate that the SOS1 inhibitor disclosed herein synergistically reduces tumor volume in combination with amivantamab in the tumor model.

[0050]

[0021] FIG. 4 shows results of a study in which mice bearing a colorectal cancer PDX model exhibiting a KRAS G12C mutation were treated with (i) a SOS1 inhibitor of the present disclosure (e.g., Compound A) alone, (ii) amivantamab alone, or (iii) a combination of (i) and (ii). The results demonstrate that the SOS1 inhibitor disclosed herein synergistically inhibits tumor growth in combination with amivantamab in a KRAS G12C mutant model.

[0051]

[0022] FIG. 5 shows results of a study in which mice bearing H820 xenograft tumors (a papillary adenocarcinoma model exhibiting EGFR L858R / T790M mutations and MET amplification) were treated with (i) a SOS1 inhibitor of the present disclosure (e.g., Compound A) alone, (ii) amivantamab alone, or (iii) a combination of (i) and (ii). The results demonstrate that the SOS1 inhibitor disclosed herein synergistically reduces tumor volume in combination with amivantamab in the tumor model.

[0052]

[0023] FIG. 6 shows results of a study in which mice bearing H820 xenograft tumors were treated with amivantamab alone for the first 22 days of the study, then amivantamab in combination with a S0S1 inhibitor of the present disclosure (e.g., Compound A) until dosing was stopped at day 53 of the study. The results demonstrate that the SOS1 inhibitor disclosed herein synergistically reduces tumor volume in combination with amivantamab in the tumor model.

[0053]

[0024] FIG. 7 shows results of a study in which mice bearing Ba / F3-EGFR-L858R+T790M+C797S allograft tumors were treated with (i) a SOS1 inhibitor of the present disclosure (e.g., Compound A) alone, (ii) amivantamab alone, or (iii) a combination of (i) and (ii). The results demonstrate that the SOS1 inhibitor disclosed herein synergistically reduces tumor volume in combination with amivantamab in the tumor model.

[0054] DETAILED DESCRIPTION

[0055]

[0025] The practice of some embodiments disclosed herein employ, unless otherwise indicated, conventional techniques of immunology, biochemistry, chemistry, molecular biology, microbiology, cell biology, genomics and recombinant DNA, which are within the skill of the art. See for example Sambrook and Green, Molecular Cloning: A Laboratory Manual, 4th Edition (2012); the series Current Protocols in Molecular Biology (F. M. Ausubel, et al. eds.); the series Methods In Enzymology (Academic Press, Inc.); PCR 2: A Practical Approach (M. J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)); Antibodies, A Laboratory Manual (Harlow and Lane, eds. (1988)); and Culture of Animal Cells: A Manual of Basic Technique and Specialized Applications, 6th Edition (R.I. Freshney, ed. (2010)).

[0026] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. In the event that there are a plurality of definitions for terms herein, those in this section prevail. All patents, patent applications, publications and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) referred to herein are incorporated by reference. Chemical structures are named herein according to IUPAC conventions as implemented in ChemDraw® software (Perkin Elmer, Inc., Cambridge, MA). The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise.

[0056]

[0027] “About” as used herein when referring to a measurable value such as an amount, a duration, and the like, is meant to encompass variations of ± 10% of a stated number or value.

[0057]

[0028] The term “Cx.y” or “Cx-Cy” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl, is meant to include groups that contain from x to y carbons in the chain. For example, the term “Cx.yalkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched- chain alkyl groups, that contain from x to y carbons in the chain.

[0058]

[0029] “Alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including linear and branched alkyl groups. An alkyl group may contain from one to twelve carbon atoms (e.g., Cm alkyl), such as one to eight carbon atoms (Cns alkyl) or one to six carbon atoms (Ci-6 alkyl). Exemplary alkyl groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. An alkyl group is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0059]

[0030] “Haloalkyl” refers to an alkyl group that is substituted by one or more halogens. Exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, tri chloromethyl, 2,2,2-trifluoroethyl, 1 ,2-difluoroethyl, 3-bromo-2- fluoropropyl, and 1 ,2-dibromoethyl.

[0060]

[0031] “Alkenyl” refers to substituted or unsubstituted hydrocarbon groups, including linear and branched alkenyl groups, containing at least one double bond. An alkenyl group may contain from two to twelve carbon atoms (e.g., C2-12 alkenyl), such as two to eight carbon atoms (C2-8 alkenyl) or two to six carbon atoms (C2-6 alkenyl). Exemplary alkenyl groups include ethenyl (i.e., vinyl), prop-l -enyl, but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0061]

[0032] “Alkynyl” refers to substituted or unsubstituted hydrocarbon groups, including linear and branched alkynyl groups, containing at least one triple bond. An alkynyl group may contain from two to twelve carbon atoms (e.g., C2- 12 alkynyl), such as two to eight carbon atoms (C2-8 alkynyl) or two to six carbon atoms (C2-6 alkynyl). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0062]

[0033] “Alkylene” or “alkylene chain” refers to substituted or unsubstituted divalent saturated hydrocarbon groups, including linear alkylene and branched alkylene groups, that contain from one to twelve carbon atoms (e.g., CM2 alkylene), such as one to eight carbon atoms (Cns alkylene) or one to six carbon atoms (Ci-6 alkylene). Exemplary alkylene groups include methylene, ethylene, propylene, and n-butylene. Similarly, “alkenylene” and “alkynylene” refer to alkylene groups, as defined above, which comprise one or more carbon-carbon double or triple bonds, respectively. The points of attachment of the alkylene, alkenylene or alkynylene chain to the rest of the molecule can be through one carbon or any two carbons of the chain. Unless stated otherwise specifically in the specification, an alkylene, alkenylene, or alkynylene group is optionally substituted by one or more substituents such as those substituents described herein.

[0063]

[0034] “Heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” refer to substituted or unsubstituted alkyl, alkenyl and alkynyl groups, respectively, in which one or more, such as 1, 2 or 3, of the carbon atoms are replaced with a heteroatom, such as O, N, P, Si, S, or combinations thereof. Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may optionally be oxidized, and any nitrogen heteroatoms may optionally be quatemized. If given, a numerical range refers to the chain length in total. For example, a 3- to 8-membered heteroalkyl group has a chain length of 3 to 8 atoms. Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl, or heteroalkynyl chain. Unless stated otherwise specifically in the specification, a heteroalkyl, hetero alkenyl, or heteroalkynyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0064]

[0035] “Hetero alkylene”, “hetero alkenylene” and “heteroalkynylene” refer to substituted or unsubstituted alkylene, alkenylene and alkynylene groups, respectively, in which one or more, such as 1, 2 or 3, of the carbon atoms are replaced with a heteroatom, such as O, N, P, Si, S, or combinations thereof. Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may optionally be oxidized, and any nitrogen heteroatoms may optionally be quatemized. If given, a numerical range refers to the chain length in total. For example, a 3- to 8- membered hetero alkylene group has a chain length of 3 to 8 atoms. The points of attachment of the heteroalkylene, hetero alkenylene or heteroalkynylene chain to the rest of the molecule can be through either one heteroatom or one carbon, or any two heteroatoms, any two carbons, or any one heteroatom and any one carbon in the heteroalkylene, hetero alkenylene or heteroalkynylene chain. Unless stated otherwise specifically in the specification, a heteroalkylene, heteroalkenylene, or heteroalkynylene group is optionally substituted by one or more substituents such as those substituents described herein.

[0065]

[0036] “Carbocycle” refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is a carbon atom. Carbocycle may include C3-10 monocyclic rings, Ce-i2 bicyclic rings, Ce-i2 spirocyclic rings, and Ce-i2 bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the carbocycle is a Ce-i2 aryl group, such as Ce-io aryl. In some embodiments, the carbocycle is a Ce-i2 cycloalkyl group. In some embodiments, the carbocycle is a Ce-i2 cycloalkenyl group. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocycle. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantly, phenyl, indanyl, and naphthyl. Unless state otherwise specifically in the specification, a carbocycle is optionally substituted by one or more substituents such as those substituents described herein.

[0066]

[0037] “Heterocycle” refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms, for example 1, 2 or 3 heteroatoms selected from O, S and N. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 6- to 12-membered spirocyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, the heterocycle is a 5- to 10-membered heteroaryl group, such as 5- or 6-membered heteroaryl. In some embodiments, the heterocycle is a 3- to 12-membered heterocycloalkyl group. In an exemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl. Unless stated otherwise specifically in the specification, a heterocycle is optionally substituted by one or more substituents such as those substituents described herein.

[0067]

[0038] “Heteroaryl” refers to a 5- to 12-membered aromatic ring that comprises at least one heteroatom, such as 1, 2 or 3 heteroatoms, selected from O, S and N. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic — including fused, spirocyclic and bridged ring systems — wherein at least one of the rings in the ring system is aromatic. The heteroatom(s) in the heteroaryl may optionally be oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryl groups include, but are not limited to, azepinyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroquinolinyl, thiadiazolyl, thiazolyl, and thienyl groups. Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted by one or more substituents such as those substituents described herein.

[0068]

[0039] Unless stated otherwise, hydrogen atoms are implied in structures depicted herein as necessary to satisfy the valence requirement.

[0069]

[0040] A waved line drawn across a bond or a dashed bond are used interchangeably herein to denote where a bond disconnection or attachment occurs. For example, in the structure R7, if R7is 1- cyclopropyl- 1 -carbonitrile as in , ”

[0070]

[0041] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or heteroatoms of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

[0071]

[0042] A compound disclosed herein, such as a compound of Formula (I), is optionally substituted by one or more, such as 1, 2 or 3 substituents selected from: halogen, oxo, =NH, -CN, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, -CH2-(C3-IO carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -OR21, -SR21, -N(R22)(R23), -C(O)OR22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, - N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, -CH2-(C3-10 carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), - N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, - S(O)2N(R22)(R23), and -OC(O)R25; R21is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6 alkyl; R22is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6 alkyl; R23is independently selected at each occurrence from H and C1-6alkyl; R24is independently selected at each occurrence from H and C1-6 alkyl; and R25is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-10 carbocycle, and 3- to 10-membered heterocycle.

[0043] In some embodiments, a compound disclosed herein, such as a compound of Formula (I), is optionallysubstituted by one or more, such as 1, 2 or 3 substituents selected from: halogen, oxo, =NH, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -OR21, -SR21, -N(R22)(R23), -C(O)OR22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, - N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -OR21, -SR21, and -N(R22)(R23); R21is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6 alkyl; R22is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6 alkyl; R23is independently selected at each occurrence from H and C1-6alkyl; R24is independently selected at each occurrence from H and C1-6 alkyl; and R25is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-10carbocycle, and 3- to 10-membered heterocycle.

[0044] In some embodiments, a compound disclosed herein, such as a compound of Formula (I), is optionallysubstituted by one or more, such as 1, 2 or 3 substituents selected from halogen, oxo, =NH, -CN, -NO2, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10- membered heterocycle), -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3, and -NHCH2CH3, wherein C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C3-10 carbocycle, -CH2-(C3-10 carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10- membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, -NO2, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3, and -NHCH2CH3.

[0045] It will be understood by those skilled in the art that substituents can themselves be substituted, ifappropriate. Unless specifically stated as “unsubstituted”, references to chemical moieties herein are understood to include substituted variants. For example, reference to a “heteroaryl” group or moiety implicitly includes both substituted and unsubstituted variants.

[0046] Where bivalent substituent groups are specified herein by their conventional chemical formulae, writtenfrom left to right, they are intended to encompass the isomer that would result from writing the structure from right to left, e.g., -CH2O- is also intended to encompass -OCH2-.

[0047] “Optional” or “optionally” means that the subsequently described event or circumstances may or may notoccur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, an “optionally substituted” group may be either unsubstituted or substituted.

[0048] Compounds of the present disclosure also include crystalline and amorphous forms of those compounds,pharmaceutically acceptable salts, and active metabolites having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, amorphous forms of the compounds, and mixtures thereof.

[0049] The compounds described herein may exhibit their natural isotopic abundance, or one or more of the atomsmay be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, denoted1H (protium),2H (deuterium), and3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism. Examples of isotopes that may be incorporated into compounds of the present disclosure include, but are not limited to,2H,3H,13C,14C,15N,18O,17O,35S,36Cl, and18F. Of particular interest are compound of Formula (I) enriched in tritium or carbon-14, which can be used, for example, in tissue distribution studies; compounds of the disclosure enriched in deuterium—especially at a site of metabolism—resulting, for example, in compounds having greater metabolic stability; and compounds of Formula (I) enriched in a positron emitting isotope, such as11C,18F,15O and13N, which can be used, for example, in Positron Emission Topography (PET) studies. Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art.

[0050] As used herein, the phrase “of the formula”, “having the formula” or “having the structure” is not intended to be limiting and is used in the same way that the term “comprising” is commonly used. For example, if one structure is depicted, it is understood that all stereoisomer and tautomer forms are encompassed, unless stated otherwise.

[0072]

[0051] Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. In some embodiments, in order to optimize the therapeutic activity of the compounds of the disclosure, e.g., to treat cancer, it may be desirable that the carbon atoms have a particular configuration (e.g., (R,R), (S,S), (S,R), or (R,S)) or are enriched in a stereoisomeric form having such configuration. The compounds of the disclosure may be provided as racemic mixtures. Accordingly, the disclosure relates to racemic mixtures, pure stereoisomers (e.g., enantiomers and diastereomers), stereoisomer-enriched mixtures, and the like, unless otherwise indicated. When a chemical structure is depicted herein without any stereochemistry, it is understood that all possible stereoisomers are encompassed by such structure. Similarly, when a particular stereoisomer is shown or named herein, it will be understood by those skilled in the art that minor amounts of other stereoisomers may be present in the compositions of the disclosure unless otherwise indicated, provided that the utility of the composition as a whole is not eliminated by the presence of such other isomers. Individual stereoisomers may be obtained by numerous methods that are known in the art, including preparation using chiral synthons or chiral reagents, resolution using chiral chromatography using a suitable chiral stationary phase or support, or by chemically converting them into diastereomers, separating the diastereoisomers by conventional means such as chromatography or recrystallization, then regenerating the original stereoisomer.

[0073]

[0052] Additionally, where applicable, all cis-trans or E / Z isomers (geometric isomers), tautomeric forms and topoisomeric forms of the compounds described herein are included with the scope of the disclosure unless otherwise specified.

[0074]

[0053] The term “pharmaceutically acceptable” refers to a material that is not biologically or otherwise unacceptable when used in the subject compositions and methods. For example, the term “pharmaceutically acceptable carrier” refers to a material — such as an adjuvant, excipient, glidant, sweetening agent, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier — that can be incorporated into a composition and administered to a patient without causing unacceptable biological effects or interacting in an unacceptable manner with other components of the composition. Such pharmaceutically acceptable materials typically have met the required standards of toxicological and manufacturing testing, and include those materials identified as suitable inactive ingredients by the U.S. Food and Drug Administration.

[0075]

[0054] The terms “salt” and “pharmaceutically acceptable salt” refer to a salt prepared from a base or an acid. Pharmaceutically acceptable salts are suitable for administration to a patient, such as a mammal (for example, salts having acceptable mammalian safety for a given dosage regime). Salts can be formed from inorganic bases, organic bases, inorganic acids and organic acids. In addition, when a compound contains both a basic moiety, such as an amine, pyridine or imidazole, and an acidic moiety, such as a carboxylic acid or tetrazole, zwitterions may be formed and are included within the term “salt” as used herein. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0076]

[0055] “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxy lie acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0077]

[0056] “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, poly amine resins and the like. See Berge et al., supra.

[0078]

[0057] As used herein, “treating” or “treatment” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition (such as cancer) in a subject, including but not limited to the following: (a) ameliorating the disease or medical condition, e.g., eliminating or causing regression of the disease or medical condition in a subject; (b) suppressing the disease or medical condition, e.g., slowing or arresting the development of the disease or medical condition in a subject; or (c) alleviating symptoms of the disease or medical condition in a subject. For example, “treating cancer” would include preventing cancer from reoccurring, ameliorating cancer, suppressing cancer, and alleviating the symptoms of cancer. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.

[0079]

[0058] A “therapeutic effect”, as that term is used herein, encompasses a therapeutic benefit and / or prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0080]

[0059] The terms “administer”, “administering”, “administration”, and derivatives thereof refer to the methods that may be used to enable delivery of a composition to the desired site of biological action. These methods include, but are not limited to parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, intrathecal, intranasal, intravitreal, infusion and local injection), transmucosal injection, oral administration, administration as a suppository, and topical administration. Administration is by any route, including parenteral. Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transplantation, etc. One skilled in the art will know of additional methods for administering a therapeutically effective amount of a composition of the present disclosure for preventing or relieving one or more symptoms associated with a disease.

[0081]

[0060] The term “effective amount” or “therapeutically effective amount” or “therapeutically effective dose” refers to the amount of an agent that is sufficient to effect beneficial or desired results. The therapeutically effective amount may vary depending upon one or more of: the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. An effective amount of an active agent may be administered in a single dose or in multiple doses. A component may be described herein as having at least an effective amount, or at least an amount effective, such as that associated with a particular goal or purpose, such as any described herein. The term “effective amount” also applies to a dose that will provide an image for detection by an appropriate imaging method. The specific dose may vary depending on one or more of: the particular agent chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to be imaged, and the physical delivery system in which it is carried.

[0082]

[0061] The terms “sub-therapeutic amount”, “sub-effective amount”, and “sub-therapeutic dose” are used interchangeably and refer to the amount of an agent that is less than the effective amount for that agent, but when combined with an effective or sub-therapeutic amount of a different agent can produce a desired result, due to, for example, synergy in the resulting efficacious effects and / or reduced side effects by the combination of (i) the sub- therapeutic amount of the agent and (ii) the different agent (e.g., one or more different agents). For example, an agent can be approved for clinical use for a specified indication at a defined dose or range thereof (e.g., 150 milligrams per day (mg / d)) over the course of one or more administrations, and a sub-therapeutic amount of such agent can be lower than the approved dose or range thereof by at least about 0.1-fold, 0.2-fold, 0.5-fold, 1-fold, 2- fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 200-fold, 500-fold, 1,000-fold, 2,000-fold, 5,000-fold, 10,000-fold, 20,000-fold, 50,000-fold, 100,000-fold, or more. The sub-therapeutic amount of such agent can be lower than the approved dose or range thereof by at most about 100,000-fold, 50,000-fold, 20,000-fold, 10,000-fold, 5,000-fold, 2,000-fold, 1,000-fold, 500-fold, 200-fold, 100-fold, 50-fold, 20-fold, 10-fold, 5-fold, 2-fold, 1-fold, 0.5-fold, 0.2- fold, 0.1 -fold or less. A sub -therapeutic amount of an agent can be achieved by reducing the amount of the agent per dosage and / or by reducing the number of administrations (or cycles) of the agent to the subject.

[0083]

[0062] The term “synergistic” or “synergizing” effect refers to when a desired effect (e.g., one or more different effects) of a combination (or combination treatment) comprising two or more different therapeutic components (e.g., two or more different therapies, two or more therapeutic agents, etc.) is greater than (i) the effect of each therapeutic component alone and / or (ii) the sum of the effect of each therapeutic component alone when administered individually (e.g., the sum of individual effects). The synergistic effect can be at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 150%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1,000%, 5,000%, or more than (i) the effect of each therapeutic component alone and / or (ii) the sum of individual effects. The effect can be any measurable effect including but not limited to an enhancement of a therapeutic effect of an individual component within the combination or a reduction in a side effect of an individual component within the combination. In some embodiments, the effect is a pharmacodynamic effect, such as phosphorylated ERK (p-ERK) and / or DUSP6 inhibition, optionally assessed in whole blood. To yield the synergistic effect, the two or more different therapeutic components of the combination treatment as disclosed herein can be administered concurrently or sequentially, as separate components or as a unit dosage. For example, a synergistic effect of a combination comprising a first agent and a second agent can yield a desired therapeutic outcome (e.g., in treating cancer) that is comparable (e.g., substantially the same) or better than (i) the therapeutic outcome of each therapeutic component alone at the therapeutically effective amount and / or (ii) the sum of individual effects, where either or both of the first and the second agent are administered in a respective sub-therapeutic amount. In another example, a synergistic effect of a combination comprising a first agent and a second agent can yield a desired therapeutic outcome (e.g., reducing side effect of either one of the agent) that is comparable (e.g., substantially the same) or better than the therapeutic outcome of each therapeutic component alone.

[0084]

[0063] The term “IC50” refers to the half maximal inhibitory amount (e.g., concentration) of an inhibitor in inhibiting a biological or biochemical effect. IC50 can be a quantitative measure that indicates how much of a particular inhibitor is needed to inhibit a given biological or biochemical effect (e.g., expression and / or activity level of a gene / protein of interest, growth, or growth rate of a cell, etc.) by substantially half (e.g., about 50%). For example, determination of IC50 can be made by determining and constructing a dose-response curve and examining the effect of different concentrations of an inhibitor on reducing cell growth (e.g., inhibiting proliferation of cancer cells), and determining the concentration of the inhibitor at which 50% inhibition of cell growth is observed.

[0085]

[0064] The term “combination”, as applied to agents including inhibitors disclosed herein, refers to the use of two or more agents (e.g., a SOS1 inhibitor and at least another inhibitor against a different signaling molecule) in vitro, in vivo, or ex-vivo. The two or more agents in combination can be formulated in one single formulation, or in separate formulation(s). A combination treatment or therapy with two or more agents can be carried out conjunctively in any temporal order, administered simultaneously or separately.

[0086]

[0065] The term “conjunction” refers to a temporal aspect of the use of two or more agents (e.g., a SOS1 inhibitor and at least another inhibitor against a different signaling molecule) in vitro, in vivo, or ex-vivo. For example, one agent of a set of agents of interest can be administered prior to, subsequent to, or concurrently with the administration of a second agent of the set. Simultaneous administration can be effectuated by simultaneously administering multiple agents as separate agents, or as a unit dosage comprising the multiple agents.

[0087]

[0066] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to a compound having the ability to inhibit a biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein (e.g., SOS1). Accordingly, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition.

[0067] The term “selective inhibition” or “selectively inhibit” refers to the ability of a biologically active agent to preferentially reduce the target signaling activity as compared to off-target signaling activity, via direct or indirect interaction with the target.

[0088]

[0068] The terms “subject”, “individual”, and “patient” are used interchangeably herein to refer to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the subject is a mammal, such as a human. “Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like. Tissues, cells, and their progeny of a biological entity obtained in vivo or cultured in vitro are also encompassed.

[0089]

[0069] The terms “therapeutic agent”, “therapeutic capable agent” or “treatment agent” are used interchangeably and refer to a molecule or compound that confers some beneficial effect upon administration to a subject. The beneficial effect includes enablement of diagnostic determinations; amelioration of a disease, symptom, disorder, or pathological condition; reducing or preventing the onset of a disease, symptom, disorder or condition; and generally counteracting a disease, symptom, disorder or pathological condition.

[0090]

[0070] The terms “polypeptide”, “peptide” and “protein” are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. As used herein the term “amino acid” refers to either natural and / or unnatural or synthetic amino acids, including glycine and both the D or L optical isomers, and amino acid analogs and peptidomimetics.

[0091]

[0071] The terms “polynucleotide”, “nucleotide”, “nucleotide sequence”, “nucleic acid” and “oligonucleotide” are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three-dimensional structure, and may perform any function, known or unknown. The following are non-limiting examples of polynucleotides: coding or noncoding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A polynucleotide may comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs, such as peptide nucleic acid (PNA), morpholino and locked nucleic acid (LNA), glycol nucleic acid (GNA), threose nucleic acid (TNA), 2 ’-fluoro, 2’-0Me, and phosphorothiolated DNA. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component or other conjugation target.

[0092]

[0072] The term “nucleic acid agent” refers to an inhibitory agent capable of downregulating (e.g., reducing or inhibiting) expression and / or activity of a target moiety (e.g., a protein or a gene encoding thereof). In some embodiments, a nucleic acid agent may consist of a nucleic acid molecule. In some embodiments, a nucleic acid agent may comprise a nucleic acid molecule. In some embodiments, a nucleic acid agent may comprise a nucleic acid molecule and a non-nucleic acid molecule. The nucleic acid molecule and the non-nucleic acid molecule may be operatively coupled to each other to yield the inhibitory effect on the target moiety. The nucleic acid molecule and the non-nucleic acid molecule may be coupled (e.g., covalently and / or non-covalently) to each other. In some cases, the nucleic acid molecule and the non-nucleic acid molecule can be linked to each other via a linker. In some cases, the nucleic acid molecule can be configured to bind to the non-nucleic acid molecule. In some cases, the non- nucleic acid molecule can be configured to bind to the nucleic acid molecule. Non-limiting examples of the non- nucleic acid molecule include a small molecule, a polypeptide (e.g., an enzyme), etc. In some cases, the non-nucleic acid molecule is a nuclease, e.g., an endonuclease.

[0093]

[0073] As used herein, “expression” refers to the process by which a polynucleotide is transcribed from a DNA template (such as into and mRNA or other RNA transcript) and / or the process by which a transcribed mRNA is subsequently translated into peptides, polypeptides, or proteins. Transcripts and encoded polypeptides may be collectively referred to as “gene product.” If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA in a eukaryotic cell.

[0094]

[0074] An “antigen” is a moiety or molecule that contains an epitope, and, as such, also specifically binds to an antibody. An “antigen binding unit” may be whole or a fragment (or fragments) of a full-length antibody, a structural variant thereof, a functional variant thereof, or a combination thereof. A full-length antibody may be, for example, a monoclonal, recombinant, chimeric, deimmunized, humanized and human antibody. Examples of a fragment of a full-length antibody may include, but are not limited to, variable heavy (VH), variable light (VL), a heavy chain found in camelids, such as camels, llamas, and alpacas (VHH or VHH), a heavy chain found in sharks (V-NAR domain), a single domain antibody (sdAb, e.g., “nanobody”) that comprises a single antigen-binding domain, Fv, Fd, Fab, Fab', F(ab')2, and “r IgG“ (or half antibody). Examples of modified fragments of antibodies may include, but are not limited to scFv, di-scFv or bi(s)-scFv, scFv-Fc, scFv-zipper, scFab, Fab2, Fab3, diabodies, single chain diabodies, tandem diabodies (Tandab's), tandem di-scFv, tandem tri-scFv, minibodies (e.g., (VH-VL- CH3)2, (scFv-CH3)2, ((scFv)2-CH3+CH3), ((scFv)2-CH3) or (scFv-CH3-scFv)2), and multibodies (e.g., tnabodies or tetrabodies).

[0095]

[0075] The term “antibody” and “antibodies” encompass any antigen binding units, including without limitation: monoclonal antibodies, human antibodies, humanized antibodies, camelised antibodies, chimeric antibodies, and any other epitope -binding fragments.

[0096]

[0076] The term “diseased cell” refers to the state of a cell, tissue, or organism that diverges from the normal or healthy state. A diseased cell may result from the influence of a pathogen, a toxic substance, irradiation, or cell internal deregulation (e.g., genetic mutation). In an example, a diseased cell is a cell that has been infected with a pathogenic virus. In an example, a diseased cell is a malignant cell or neoplastic cell that may constitute or give rise to cancer in a subject (e.g., a mammal such as a human subject).

[0097]

[0077] “Prodrug” is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein (e.g., a compound of Formula (I)). Thus, the term “prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In some aspects, a prodrug is inactive when administered to a subject but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam); Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” (1987) A.C.S. Symposium Series, Vol. 14; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press each of which is incorporated in full by reference herein). The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are typically prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of a hydroxy functional group, or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound, and the like.

[0098]

[0078] The term “in vivo” refers to an event that takes place in a subject’s body. The term “ex vivo” refers to an event that first takes place outside of the subject’s body for a subsequent in vivo application into a subject’s body. For example, an ex vivo preparation may involve preparation of cells outside of a subject’s body for the purpose of introduction of the prepared cells into the same or a different subject’s body. The term “in vitro” refers to an event that takes place outside of a subject’s body. For example, an in vitro assay encompasses any assay run outside of a subject’s body. In vitro assays encompass cell-based assays in which cells alive or dead are employed. In vitro assays also encompass a cell-free assay in which no intact cells are employed.

[0099]

[0079] The disclosure is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the disclosure includes compounds produced by a process comprising administering a compound disclosed herein to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the disclosure in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to a human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.

[0100]

[0080] The term “Ras” or “RAS” refers to a protein in the Rat sarcoma (Ras) superfamily of small GTPases, such as in the Ras subfamily. The Ras superfamily includes, but is not limited to, the Ras subfamily, Rho subfamily, Rab subfamily, Rap subfamily, Arf subfamily, Ran subfamily, Rheb subfamily, RGK subfamily, Rit subfamily, Miro subfamily, and Unclassified subfamily. In some embodiments, a Ras protein is selected from the group consisting of KRAS (K-Ras or K-ras or Kras), ERAS (or H-Ras), NRAS (or N-Ras), MRAS (or M-Ras), ERAS (or E-Ras), RRAS2 (or R-Ras2), RALA (or RalA), RALB (or RalB), RIT1, and any combination thereof, such as from KRAS, HRAS, NRAS, RALA, RALB, and any combination thereof.

[0101]

[0081] “Amivantamab” and “amivantamab-vmjw” are used interchangeably herein to refer to a low-fucose human immunoglobulin G1 -based bispecific antibody directed against the EGF and MET receptors that has a molecular weight of approximately 148 kDa. Amivantamab may be produced by mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology. Amivantamab is sold under the brand name Rybrevant as an injection for intravenous infusion and is indicated for the treatment of adult patients with locally advanced or metastatic nonsmall cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.

[0102] Rybrevant injection is a sterile, preservative-free, colorless to pale yellow solution in single-dose vials having a pH of approximately 5.7. Each Rybrevant vial contains 350 mg (50 mg / mL) amivantamab-vmjw, EDTA disodium salt dihydrate (0.14 mg), L-histidine (2.3 mg), L-histidine hydrochloride monohydrate (8.6 mg), L-methionine (7 mg), polysorbate 80 (4.2 mg), sucrose (595 mg), and water for injection, USP. The recommended dosage of Rybrevant is based on baseline body weight and administered as an intravenous infusion after dilution. For patients weighing less than 80 kg, a dose of 1050 mg (3 vials) is recommended, and for patients weighing greater than or equal to 80 kg, a dose of 1400 mg (4 vials) is recommended.

[0103] Methods

[0104]

[0082] The SOS1 inhibitors and the pharmaceutical compositions thereof, as disclosed herein, are particularly useful in treating epidermal growth factor receptor (EGFR)-mediated diseases and the symptoms associated therewith. Common EGFR mutations, including variable deletions of at least three amino acid residues in exon 19 (exon 19 deletion), L858R point mutation in exon 21, and exon 20 insertion mutations (ex20ins), are activating mutations that result in constitutive activation of EGFR and downstream signaling pathways, particularly in nonsmall cell lung cancer (NSCLC). Cancers harboring exon 19 deletions and L858R mutations are typically more sensitive to EGFR inhibitors, such as gefitinib and erlotinib, as compared to cancers in which no EGFR mutations are detected. However, insertions in exon 20 result in constitutive activation of EGFR, are associated with resistance to EGFR inhibitors, and correlate with a poor patient prognosis. The compositions and methods disclosed herein open a new avenue for remission or treatment free remission (TFR) for EGFR-mediated cancers, and in particular NSCLC in which an exon 19 deletion, L858R mutation, T790M mutation, C797S mutation, and / or exon 20 insertion is detected.

[0105]

[0083] In one aspect, the present disclosure provides a method of reducing proliferation of cancer cells comprising an epidermal growth factor receptor (EGFR) exon 20 insertion, the method comprising administering to the cells (a) a SOS1 inhibitor and (b) amivantamab, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b). In some embodiments, the cancer cells are non-small cell lung cancer cells.

[0106]

[0084] In another aspect, the present disclosure provides a method of downregulating EGFR signaling output in a plurality of non-small cell lung cancer cells, comprising: (i) assessing EGFR mutation status in a biological sample comprising nucleic acid from the subject; and (ii) administering an effective dose of (a) a SOS1 inhibitor and an effective dose of (b) amivantamab if an EGFR exon 20 insertion is detected in the sample, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b).

[0107]

[0085] In another aspect, the present disclosure provides a method of treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy, the method comprising administering to the subject (a) a SOS1 inhibitor and (b) amivantamab.

[0108]

[0086] In yet another aspect, the present disclosure provides a method of treating an EGFR-mediated disease or condition or ameliorating the symptoms thereof in a subject in need thereof. The method may comprise administering to the subject (a) a SOS1 inhibitor and (b) amivantamab. In some embodiments, the disease or condition is a cancer comprising an EGFR mutation, including but not limited to an exon 19 deletion, an L858R mutation, a T790M mutation, a C797S mutation, and / or an exon 20 insertion. In some embodiments, the cancer comprises an exon 20 insertion. In certain aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject (a) a SOS1 inhibitor and (b) amivantamab, optionally wherein the cancer comprises an EGFR mutation, such as an exon 19 deletion, L858R, T790M, C797S, and / or an exon 20 insertion. In some embodiments, the cancer exhibits MET amplification. In certain aspects, the present disclosure provides a method of treating an EGFR-mediated cancer in a subject, comprising administering to the subject a pharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (I- 1 ), or a pharmaceutically acceptable salt or solvate thereof, (ii) amivantamab, and (iii) a pharmaceutically acceptable excipient.

[0109]

[0087] In still another aspect, the present disclosure provides a method of treating an EGFR-mediated cancer in a subject, comprising administering to the subject (a) a SOS1 inhibitor and (b) amivantamab, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b). In some embodiments, administration of (a) and (b) synergistically reduces proliferation of the cancer cells with a synergistic value of at least 0.1 as ascertained by Bliss independence criterion.

[0110]

[0088] Any method described herein that comprises administering (a) a SOS1 inhibitor and (b) amivantamab may further comprise administering (c) an additional agent or additional therapy. Suitable agents that can be administered in combination with (a) the SOS1 inhibitor and (b) amivantamab include other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, immunomodulatory agents, steroids, chemotherapeutic agents, and combinations thereof. In some embodiments, the additional therapy is selected from surgery, cell therapy, chemotherapy, and radiation.

[0111]

[0089] The EGFR-mediated disease or condition may be any disease or condition in which the EGFR signaling pathway contributes to the progression of the disease or condition. In some embodiments, the disease or condition is characterized by aberrant activation of EGFR, optionally due to EGFR amplification, EGFR overexpression, overexpression of EGFR ligands, and / or occurrence of one or more EGFR mutation. EGFR-mediated diseases or conditions include, but are not limited to: cancer, such as lung adenocarcinoma, squamous cell lung carcinoma, nonsmall cell lung cancer, anal cancer, ovarian cancer, breast cancer, colorectal cancer, bladder cancer, esophageal cancer, glioblastoma, and head and neck carcinomas; inflammatory disease, such as psoriasis, eczema, atopic dermatitis, and atherosclerosis; and renal disease, such as renal fibrosis, chronic kidney disease, acute kidney injury, obstructive nephropathy, diabetic nephropathy, hypertensive nephropathy, and glomerulonephritis. In some embodiments, the EGFR-mediated disease or condition is an EGFR-mediated cancer. In some embodiments, the cancer is lung cancer, such as non-small cell lung cancer. In some embodiments, the cancer is metastatic, such as metastatic NSCLC. In some embodiments, the cancer is locally advanced, such as locally advanced NSCLC. In some embodiments, the cancer comprises an EGFR mutation, such as a mutation selected from L858R, T790M, C797S, an exon 19 deletion, and an exon 20 insertion. In some embodiments, the cancer comprises an exon 20 insertion. In some embodiments, the cancer comprises a double or triple EGFR mutant, such as T790M / C797S, L858R / T790M, dell9 / T790M / C797S, or L858R / T790M / C797S. In some embodiments, the cancer comprises aberrant MET expression, such as overexpression of MET or MET amplification.

[0112]

[0090] Determining whether a tumor or cancer comprises an EGFR mutation can be undertaken by assessing the nucleotide sequence encoding the protein, by assessing the amino acid sequence of the protein, or by assessing the characteristics of a putative protein. Exemplary nucleic acid assays include but are not limited to genotyping assays and sequencing methods. Sequencing methods can include next-generation sequencing, targeted sequencing, exome sequencing, whole genome sequencing, massively parallel sequencing, and the like. Several platforms for next generation sequencing are commercially available, including those marketed by Illumina and Pacific Biosciences. Additional nucleic acid assays include but not limited to in situ hybridization (e.g., FISH), polymerase chain reaction (PCR), quantitative PCR (qPCR), quantitative real-time PCR (qRT-PCR), and ligase chain reaction (LCR), all of which are applicable for detecting a genetic aberration in EGFR. Where desired, one or more nucleic acids can be employed to detect a genetic aberration resulting in formation of EGFR gene including but not limited to translation, as well as genetic mutations within the EGFR gene via point mutation, insertion, deletion, or frameshift.

[0091] Additional methods for detecting a nucleotide sequence of a gene include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high resolution melting assays, and microarray analyses. In some embodiments, the EGFR mutation is identified using a direct sequencing method of specific regions in the gene. This technique can identify all possible mutations in the region sequenced. Methods for detecting a mutant EGFR protein include, but are not limited to, detection of a mutant protein using a binding agent (e.g., an antibody) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing. In some embodiments, the EGFR mutation is identified using a PCR-based or next-generation sequencing (NGS)-based diagnostic. In some embodiments, the EGFR mutation is identified using a PCR-based diagnostic. In some embodiments, the EGFR mutation is identified using a NGS-based diagnostic.

[0113]

[0092] In some embodiments, the presence of an EGFR mutation, such as an exon 19 deletion, an exon 21 L858R substitution mutation, and / or T790M, is determined in a tumor or plasma specimen using an FDA-approved test, such as the cobas EGFR Mutation Test vl (Roche Molecular Systems, Inc.), cobas EGFR Mutation Test v2 (Roche Molecular Systems, Inc.), FoundationOne CDx (Foundation Medicine, Inc.), FoundationOne Liquid CDx (Foundation Medicine, Inc.), Guardant360 CDx (Guardant Health, Inc.), ONCO / Reveal Dx Lung & Colon Cancer Assay (O / RDx-LCCA, Pillar Biosciences, Inc.), Oncomine Dx Target Test (Life Technologies Corporation), or therascreen EGFR RGQ PCR Kit (Qiagen Manchester, Ltd.). In some embodiments, the presence of an EGFR mutation, such as L861Q, G719X, and / or S7681, is determined in a tumor or plasma specimen using an FDA- approved test, such as the therascreen EGFR RGQ PCR Kit (Qiagen Manchester, Ltd.). In some embodiments, EGFR protein expression is assessed in a tumor or plasma specimen using an FDA-approved test, such as the Dako EGFR pharmDx Kit (Dako North America, Inc.). In some embodiments, the presence of an EGFR mutation, such as an exon 20 insertion mutation, is determined in a tumor or plasma specimen using an FDA-approved test, such as the FoundationOne Liquid CDx (Foundation Medicine, Inc.), Guardant360 CDx (Guardant Health, Inc.), or Oncomine Dx Target Test (Life Technologies Corporation).

[0114]

[0093] Methods for determining whether a disease or condition is mediated by or exhibits dependence on a polypeptide such as EGFR or MET are known to those of skill in the art. These methods include, but are not limited to, cell proliferation assays, transcriptomic assays, such as RNA seq or hybridization assays, and protein detection assays, such as immunoassays. In some embodiments, an EGFR-mediated disease or condition is one comprising a known EGFR activating mutation, such as an exon 19 deletion, L858R, T790M, or an exon 20 insertion. A variety of techniques for protein analysis can also be applied for assessing the presence and / or overexpression of EGFR or mutants thereof, as well as expression of other proteins associated with EGFR TKI resistance. Suitable protein assays include, without limitation, immunohistochemistry (IHC), ELISA (enzyme linked immunosorbent assays), “sandwich” immunoassays, immunoradiometric assays, in situ immunoassays, western blot analysis, immunoprecipitation assays, immunofluore scent assays, flow cytometry, confocal microscopy, enzymatic assays, surface plasmon resonance, and PAGE-SDS. One or more of these protein assays utilize antibodies or fragments thereof that exhibit specific binding to EGFR polypeptides. A large number of anti-EGFR antibodies are available, including those provided by Thermofisher and Abeam. Commercially available antibodies can also be used in immunoassays to ascertain a decrease in EGFR TKI binding affinity to EGFR as a result of a genetic mutation in the EGFR gene.

[0094] Methods for determining whether a tumor or cancer comprises an EGFR mutation can use a variety of samples. In some embodiments, the sample is taken from a subject having a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is processed to a cell lysate. In some embodiments, the sample is processed to DNA or RNA. In some embodiments, the sample is a plasma sample. In some embodiments, the sample comprises cell-free DNA (cfDNA). In some embodiments, the method utilizes circulating cfDNA from plasma of peripheral whole blood collected from the subject.

[0115]

[0095] In practicing a subject method, the presence of EGFR gene, mutations within the EGFR gene, or other genetic aberrations associated with resistance to an EGFR TKI, can be determined using any biological sample comprising the target cells (e.g., cancer cells from a subject under investigation) or constituents thereof (e.g., constituents such as cfDNA from the tumor tissue or cancer cells). The biological sample may be a liquid biological sample or a solid biological sample from the subject under investigation or treatment. The biological sample may be a biopsy sample that is fixed, paraffin-embedded, fresh, or frozen. The biological sample may be obtained by any suitable means, including but not limited to blood draw, needle aspiration, fine needle aspiration, core needle biopsy, vacuum assisted biopsy, large core biopsy, incisional biopsy, excisional biopsy, punch biopsy, shave biopsy, skin biopsy, surgical specimen, and venipuncture.

[0116]

[0096] Depending on the tumor tissue or cancer cells to be treated, the biological sample can be obtained from, without limitation, blood or plasma, skin, heart, lung, kidney, bone marrow, breast, pancreas, liver, muscle, smooth muscle, bladder, gall bladder, colon, intestine, brain, prostate, esophagus, thyroid, serum, saliva, urine, gastric and digestive fluid, tears, stool, semen, vaginal fluid, interstitial fluids derived from tumorous tissue, ocular fluids, sweat, mucus, earwax, oil, glandular secretions, spinal fluid, hair, fingernails, plasma, nasal swab or nasopharyngeal wash, spinal fluid, cerebral spinal fluid, tissue, throat swab, biopsy, placental fluid, amniotic fluid, cord blood, emphatic fluids, cavity fluids, sputum, pus, microbiota, meconium, breast milk, and / or other excretions or body tissues of the subject.

[0117]

[0097] In some embodiments, a biological sample comprises cell-free DNA (cfDNA) derived from a whole blood or plasma of the subject. A sample may be analyzed directly for its contents, or may be processed to purify one or more of its contents for analysis. In some embodiments, the purified component of the biological sample is protein (e.g. total protein, cytoplasmic protein, or membrane protein). In some embodiments, the purified component of the sample is a nucleic acid, such as DNA (e.g. genomic DNA, cDNA, ctDNA, or cfDNA) or RNA (e.g. total RNA, mRNA, or microRNA).

[0118]

[0098] EGFR exon 20 insertions include in-frame insertions within exon 20 of EGFR. In some embodiments, an EGFR exon 20 insertion is found between residues E762 and C775. In some embodiments, an EGFR exon 20 insertion is found after E762, A763, Y764, V765, M766, A767, S768, V769, D770, N771, P772, H773, V774, or C775. In some embodiments, an EGFR exon 20 insertion is found after residue L747, A763, Y764, M766, A767 , V769, D770, P772, or H773. In some embodiments, an EGFR exon 20 insertion is found after residue V769 or D770. In some embodiments, an EGFR exon 20 insertion is selected from A763_Y764ins, Y764_V765ins, M766_A767ins, A767_V769dup, V769_D770ms, D770_N771ms, delD770ms, P772_H773ms, P772_V774ms, and H773_V774ins. In some embodiments, an EGFR exon 20 insertion is selected from D770_N771ins and V769_D770ins. In some embodiments, an EGFR exon 20 insertion is selected from delL747_P753insS, A763_Y764insFQEA, Y764_V765msHH, M766_A767insAI, M766_A767insASV, A767_V769dupASV, V769_D770insASV, D770_N771insGL, D770_N771insGT, D770_N771insNPG, D770_N771insSVD, delD770insGY, P772_H773insYNP, P772_V774insPHV, H773_V774insH, and H773_V774insNPH. In some embodiments, an EGFR exon 20 insertion is selected from D770_N771insSVD and V769_D770insASV. In some embodiments, an EGFR exon 20 insertion consists of one to four amino acid residues, such as one, two, three or four amino acid residues. In some embodiments, a cancer comprising an EGFR exon 20 insertion is insensitive to treatment with gefitinib or erlotinib.

[0099] A synergistic effect of a given combination treatment can be characterized by a synergistic value asascertained by an “excess over Bliss independence” or “BLISS” independence criterion. The Bliss independence criterion can be used to screen for candidate drug combinations. The criterion can compare the observed combination response with the predicted combination response, which predicted combination response is obtained based on the assumption that there is no effect from drug-drug interactions. The combination effect can be determined to be synergistic when the observed combination response is greater than the predicted combination response (e.g., greater by a threshold value). To determine a synergistic value of a combination treatment comprising inhibitor (a) (e.g., a SOS1 inhibitor) and inhibitor (b) (e.g., amivantamab) for inducing growth inhibition of target cells (e.g., NSCLC cells), the Bliss independence criterion can utilize the following equation: YAB,O-YAB,P(1) wherein: YAB,O is observed percent growth inhibition of the target cells by the combination comprising (a) at dose A and (b) at dose B; and YAB,Pis predicted percent growth inhibition of the target cells by the combination comprising (a) at dose A, and (b) at dose B, wherein: YAB,P = YA + YB – YAYB (2) wherein further: YAis observed percent growth inhibition of the target cells by (a) alone at dose A; YB is observed percent growth inhibition of the target cells by (b) alone at dose B; and YAYB is the product of YA and YB. The observed combined percent inhibition YAB,Ois compared with the predicted percentage growth inhibition YAB,Pin accordance with equation (1). The comparison can determine whether the combination treatment promotes a synergistic effect, an additive effect, or an antagonistic effect, as summarized in equation (3). When YAB,O > YAB,P, the combination treatment can be determined to be more efficacious than expected (e.g., a synergistic effect). When YAB,O< YAB,P, the combination treatment can be determined to be worse than expected (e.g., an antagonistic effect). When YAB,O= YAB,P, the combination treatment can be determined to be substantially the same as a simple addition of two separate drugs (e.g., independent effects, or an additive effect). >YAB,PSynergy YAB,P{= YAB,PIndependent (3) <YAB,PAntagonism

[0100] When using the Bliss independence criterion, the percent growth inhibition of the target cells can beprovided based on a percentage scale (e.g., between about 0% to about 100%) or a fractional scale (e.g., between about 0 to 1). For example, a 75% growth inhibition of the target cells can be expressed as 0.75 for purposes of analysis in accordance with the Bliss independence criterion. For example, when the fractional scale is used, the difference between the observed combined percent inhibition YAB,Oand the predicted percent growth inhibition YAB,P, in accordance with equation (1) (e.g., based on one or more in vitro experiments), can be determined to be additive (or antagonistic) when the difference is less than or equal to zero. Such difference can be determined to be synergistic when the difference is greater than zero. Here, the synergistic effect can be divided into a plurality of sub-ranges, e.g., a first synergistic sub-range having the difference between about 0.05 and about 0.1 (e.g., mild synergy), a second synergistic sub-range having the difference between about 0.1 and about 0.2 (e.g., moderate synergy), and a third synergistic sub-range having the difference greater than or equal to 0.2 (e.g., robust synergy).

[0119]

[0101] In some embodiments, the combination treatment comprising a plurality of agents (e.g., a SOS1 inhibitor disclosed or exemplified herein and amivantamab), can be utilized to reduce growth or proliferation of target cells, such as NSCLC cells, in vitro or in vivo. The therapeutic efficacy of the combination treatment can be characterized by a synergistic value of above 0. 1 as ascertained by the Bliss independence criterion. The therapeutic efficacy of the combination treatment can be characterized by a synergistic value of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, 13, 14, 15, or above as ascertained by the Bliss independence criterion. The therapeutic efficacy of the combination treatment can be characterized by a synergistic value of about 0.1 to about 1, about 1.0 to about 5, about 5 to about 10, or about 10 to about 15. In some embodiments, the synergistic value is at least 0.4, such as at least 1. In some embodiments, the synergistic value is at least 5.

[0120]

[0102] In some embodiments, the subject is a naive subject that has not been treated for the cancer. In some embodiments, the naive subject has not been treated with a TKI against EGFR prior to administering (a) and (b). In some embodiments, the subject has been treated with chemotherapy. In some embodiments, the subject has received surgery to treat the cancer. In some embodiments, the subject has not been treated with chemotherapy. In some embodiments, the subject has not received surgery. In some embodiments, the subject has been treated with a non- amivantamab TKI against EGFR prior to administering (a) and (b). In some embodiments, the subject has not been treated with amivantamab as a TKI prior to administering (a) and (b).

[0121]

[0103] In some embodiments, a subject suitable for a treatment method of the present disclosure has previously been treated with one or more tyrosine kinase inhibitor (TKI) against EGFR prior to administering (a) and (b). In some embodiments, the subject has previously been treated with a first-generation EGFR TKI (e.g., gefitinib), a second generation EGFR TKI (e.g., afatinib), or a third generation EGFR TKI (e.g., osimertinib). In some embodiments, the subject has previously been treated with a non-exon 20 insertion EGFR TKI, such as gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, neratinib, cetuximab, panitumumab, lapatinib, necitumumab, nazartinib, vandetanib, BLU-945, or zorifertinib. In some embodiments, the subject has previously been treated with gefitinib, erlotinib, or afatinib. In some embodiments, the subject has previously been treated with osimertinib. In some embodiments, the subject has previously been treated with an EGFR exon 20 insertion TKI, such as poziotinib, mobocertinib, amivantamab, zipalertinib, sunvozertinib, BAY-2927088, BLU-451, or STX-721. In some embodiments, the subject has previously been treated with amivantamab. In some embodiments, the subject has previously been treated with an EGFR TKI selected from gefitinib, erlotinib, afatinib, lazertinib, osimertinib, dacomitinib, neratinib, cetuximab, panitumumab, lapatinib, necitumumab, nazartinib, vandetanib, BLU-945, zorifertinib, poziotinib, mobocertinib, amivantamab, zipalertinib, sunvozertinib, BAY-2927088, BLU-451, and STX-721. In some embodiments, a subject suitable for a treatment method of the present disclosure has previously been treated with chemotherapy prior to administering (a) and (b). In some embodiments, the disease of the subject has progressed on or after chemotherapy. In some embodiments, a subject suitable for a treatment method of the present disclosure has previously been treated with platinum-based chemotherapy prior to administering (a) and (b). In some embodiments, the disease of the subject has progressed on or after platinum-based chemotherapy. In some embodiments, the subject has undergone tumor resection.

[0122]

[0104] Despite the remarkable progress via the advent of several generations of EGFR TKIs, drug resistance and / or intolerance to the earlier generations of TKIs severely limit treatment options to subjects who exhibit resistance or intolerance to one or more EGFR TKI, or relapse following treatment with one or more EGFR TKI. Resistance to an EGFR TKI may be characterized by one or more changes selected from (1) progression of the cancer, (2) EGFR gene mutation including point mutation, insertion, deletion, and translocation, (3) loss of EGFR T790M mutation, (4) EGFR gene amplification, {S') MET amplification, (6) HER2 amplification, (7) RAS-MAPK pathway activation, (8) PI3K pathway activation, (9) cell-cycle gene alteration, (10) oncogenic fusion, (11) histologic transformation, and (12) phenotypic transformation. In some embodiments, resistance to an EGFR TKI is characterized by an exon 20 insertion resulting in a decrease in TKI binding affinity to EGFR. In some embodiments, a subject resistant to an EGFR TKI comprises one or more mutation selected from L858R, T790M, C797S, an exon 19 deletion, and an exon 20 insertion. In some embodiments, a subject resistant to an EGFR TKI comprises a double or triple EGFR mutant, including but not limited to T790M / C797S, L858R / T790M, dell9 / T790M / C797S, and L858R / T790M / C797S.

[0123]

[0105] In some embodiments, a subject suitable for a treatment method of the present disclosure exhibits intolerance to an EGFR TKI. Amivantamab is known to cause a number of side effects, including back pain, bleeding gums, blistering, crusting, irritation, itching, or reddening of the skin, blood in the urine, bloody nose, burning, crawling, itching, numbness, painful, prickling, "pins and needles", or tingling feelings, chest pain or tightness, chills, cough, coughing or spitting up blood, cracked, dry, or scaly skin, dry, itching skin, fever, flushing, headache, loosening of the fingernails, muscle or bone pain, nausea and vomiting, nerve pain, rash with flat lesions or small raised lesions on the skin, redness or soreness around the fingernails, sneezing, swelling, trouble breathing, unsteadiness or awkwardness, and / or weakness in the arms, hands, legs, or feet. In some embodiments, the side effects of amivantamab include rash, pruritus, dry skin, fatigue, edema, pyrexia, paronychia, pneumonia, musculoskeletal pain, dyspnea, cough, nausea, stomatitis, constipation, vomiting, diarrhea, abdominal pain, hemorrhage, decreased appetite, peripheral neuropathy, dizziness, and / or headache, any or all of which may render the subject intolerant to EGFR TKI treatment.

[0124]

[0106] A subject resistant to treatment with an EGFR TKI may exhibit progression of the disease or condition, such as cancer (e.g., NSCLC), despite treatment with the EGFR TKI. An exemplary EGFR-mediated cancer is NSCLC, which typically manifests one or more symptoms which may include a cough, coughing up blood, chest pain or discomfort, trouble breathing, wheezing, hoarseness, loss of appetite, unexplained weight loss, fatigue, trouble swallowing, and swelling in the face and / or veins in the neck. Progression of NSCLC may be observed using one or more imaging methods, such as CT, PET, or MRI scans or a bronchoscopy.

[0125]

[0107] Progression may be established by a lack of reduction in any or some of the symptoms disclosed herein or known in the art that are associated with an EGFR-mediated cancer, such as NSCLC. In some embodiments, progression is established for a lack of reduction in one or more symptoms after, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months from the initial treatment of EGFR TKI.

[0126]

[0108] In some embodiments, a subject suitable for a treatment method of the present disclosure suffers from a relapse of an EGFR-mediated cancer, such as lung cancer. In some embodiments, the subject suffers from a relapse of NSCLC. A relapse can be established by a renewed onset of any of the symptoms associated with the cancer with which the subject has previously been diagnosed, or by the detection of the cancer via a suitable method, such as a CT scan, a PET scan, an MRI, a bronchoscopy, or a lung biopsy. A relapse may occur, e.g., 3, 5, 7, 8, 9, 10, 11, 12, 15, 18, 24, 25, 26, 27, 28, 29, 30, 36, or more months after the initial treatment with EGFR TKI.

[0127]

[0109] In practicing a subject method disclosed herein, administrating a S0S1 inhibitor or a pharmaceutical composition comprising an effective amount of a S0S1 inhibitor typically involves contacting a cell with a SOS1 inhibitor disclosed herein. The SOS1 inhibitor can be a small molecule, a nucleic acid agent, or a polypeptide (e.g., an endonuclease). The contacting, as disclosed herein, can occur in vitro, ex vivo, or in vivo.

[0128] [HO] In some embodiments, the cell is contacted with (i) a SOS1 inhibitor disclosed herein and (ii) amivantamab. Contacting with (i) and (ii) can take place conjunctively. For example, a SOS1 inhibitor can be administered prior to, subsequent to, or concurrently with the administration of amivantamab. For simultaneous contacting, the SOS1 inhibitor and amivantamab can be in the same composition (e.g., as a formulation or as a unit dosage) or in different compositions (e.g., subjecting the cell to two different compositions at the same time). For sequential contacting, the SOS1 inhibitor and amivantamab can be in the same composition (e.g., a single composition exhibiting different release profiles or in different compositions). For sequential contacting, a first contacting of the cell (e.g., with the SOS1 inhibitor or amivantamab) and a second contacting of the cell (e.g., with amivantamab or the SOS1 inhibitor) can be separated by at least about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 16 hours, 24 hours, 1 day, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, or longer. The first contacting and the second contacting can be separated by at most about 1 month, 1 week, 24 hours, 20 hours, 16 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 60 minutes, or less. In practicing any of the subject methods, (a) and (b) may be administered in the same formulation. In some embodiments, (a) and (b) are administered in separate formulations.

[0129] [Hl] Suitable agents that can be administered in combination with a subject SOS1 inhibitor and amivantamab include but are not limited to EGFR TKIs disclosed herein, other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, immunomodulatory agents, steroids, chemotherapeutic agents, and combinations thereof. In some embodiments, a MET inhibitor is administered in combination with a subject SOS1 inhibitor and amivantamab.

[0130]

[0112] Exemplary immunomodulatory agents include but are not limited to immuno stimulatory agents, checkpoint immune blockade agents (e.g., blockade agents or inhibitors of immune checkpoint genes, such as, for example, PD- 1, PD-L1, CTLA-4, IDO, TIM3, LAG3, TIGIT, BTLA, VISTA, ICOS, KIRs and CD39), radiation therapy agents, chemotherapy agents, and combinations thereof. In some embodiments, the immunostimulatory agents are selected from the group consisting of IL- 12, an agonist costimulatory monoclonal antibody, and combinations thereof. In one embodiment, the immuno stimulatory agent is IL- 12. In some embodiments, the agonist costimulatory monoclonal antibody is selected from the group consisting of an anti -4- IBB antibody (e.g., urelumab, PF-05082566), an anti- 0X40 antibody (pogalizumab, tavolixizumab, PF-04518600), an anti-ICOS antibody (BMS986226, MEDI-570, GSK3359609, JTX-2011), and combinations thereof. In one embodiment, the agonist costimulatory monoclonal antibody is an anti-4- IBB antibody. In some embodiments, the checkpoint immune blockade agents are selected from the group consisting of anti-PD-Ll antibodies (atezolizumab, avelumab, durvalumab, BMS-936559), anti- CTLA-4 antibodies (e.g., tremelimumab, ipilimumab), anti-PD-1 antibodies (e.g., pembrolizumab, nivolumab), anti- LAG3 antibodies (e.g., C9B7W, 410C9), anti-B7-H3 antibodies (e.g., DS-5573a), anti-TIM3 antibodies (e.g., F38- 2E2), and combinations thereof. In one embodiment, the checkpoint immune blockade agent is an anti-PD-L 1 antibody.

[0131]

[0113] Exemplary chemotherapeutic agents include an anthracycline (e.g., doxorubicin (e.g., liposomal doxorubicin)), a vinca alkaloid (e.g., vinblastine, vincristine, vindesine, vinorelbine), an alkylating agent (e.g., cyclophosphamide, decarbazine, melphalan, ifosf amide, temozolomide), an immune cell antibody (e.g., alemtuzamab, gemtuzumab, rituximab, ofatumumab, tositumomab, brentuximab), an antimetabolite (including, e.g., folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors (e.g., fludarabine)), a TNFR glucocorticoid induced TNFR related protein (GITR) agonist, a proteasome inhibitor (e.g., aclacinomycin A, gliotoxin or bortezomib), an immunomodulator such as thalidomide or a thalidomide derivative (e.g., lenalidomide). Additional chemotherapeutic agents contemplated for use in combination include busulfan (Myleran®), busulfan injection (Busulfex®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), mitoxantrone (Novantrone®), Gemtuzumab Ozogamicin (Mylotarg®), anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), dexamethasone, docetaxel (Taxotere®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxy citidine), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (EL SPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90 / MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6- thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hy camptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

[0132]

[0114] In some embodiments, a method described herein that comprises administering (a) a SOS 1 inhibitor and (b) amivantamab further comprises administering (c) an additional agent selected from (1) a SHP2 inhibitor (e.g., 6-(4- amino-4-methylpiperidin-l-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine, RMC-4630, ERAS-601, TNO155, JAB- 3068, IACS-13909 / BBP-398, SHP099, RMC-4550), (2) an inhibitor of wildtype or mutant RAS, such as wildtype KRAS, wildtype ERAS, wildtype NRAS, mutant KRAS, mutant ERAS, mutant NRAS, KRAS G12C, KRAS G12D, KRAS G12S, KRAS G12V, KRAS G13D, KRAS G13C, KRAS G13V, or KRAS Q61E (e.g., LY3537982, JAB-21822, BBO-8520, D-1553, BI-1823911, RMC-9805, MRTX1133, MRTX849, AMG510, GDC-6036, AZD4625, JDQ443, RMC-6291, RMC-6236, BI-2493, MK-1084, RMC-8839, SERI 127, JAB-21822, GFE925, IBI351, BPI-421286, JMKX1899, EBI-2438, D3S-001, GFE375, VS-7375, RMC-7977, RMC-5127, FMC-376), and (3) a MET inhibitor (e.g., foretinib, AMG-458, tivantinib, crizotinib, cabozantinib, tepotinib, capmatinib, savolitinib, glesatinib).

[0133]

[0115] A MET inhibitor for use in the present disclosure can be any MET inhibitor that is known in the art, and can include any entity that, upon administration to a subject, results in downregulation of MET in the subject. For example, a suitable MET inhibitor can be selected from a variety of types of molecules. In particular, the MET inhibitor can be a biological or chemical compound, such as a simple or complex organic or inorganic molecule, peptide, peptido mimetic, protein (e.g., antibody), liposome, or a polynucleotide (e.g., small interfering RNA, short hairpin RNA, microRNA, antisense, aptamer, ribozyme, triple helix). In some embodiments, a method disclosed herein utilizes a small molecule MET inhibitor. Exemplary MET inhibitors for use in such combinations include one or more of foretinib, AMG-458, tivantinib, crizotinib, cabozantinib, tepotinib, capmatinib, and glesatinib. In some embodiments, the MET inhibitor is selected from capmatinib, tepotinib, and cabozantinib.

[0134]

[0116] The practice of any treatment methods disclosed herein may involve administering a SOS1 inhibitor and amivantamab in combination or in conjunction with an additional therapy. Applicable therapies for treating EGFR- mediated diseases (including NSCLC) include surgery, radiotherapy, cell therapy, chemotherapy, bone marrow transplant, and radiation.

[0135]

[0117] The subject combination therapy comprising a plurality of different therapeutic agents (e.g. a SOS1 inhibitor and amivantamab) can synergistically achieve one or more desired therapeutic actions or outcomes, including, but not limited to, reduced progression of NSCLC. In some embodiments, the reduced progression of EGFR-mediated cancer is evidenced by disease stabilization, disease regression, improved lung function, or improvement of one or more symptoms of the cancer, such as improvement in one or more symptoms selected from a cough, coughing up blood, chest pain or discomfort, trouble breathing, wheezing, hoarseness, loss of appetite, unexplained weight loss, fatigue, trouble swallowing, and swelling in the face and / or veins in the neck. A subject treated according to a method of the present disclosure may exhibit one or more desired therapeutic outcomes described herein, any of which may persist for at least 1 month, such as at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, or longer. For example, a subject treated according to a method of the present disclosure may exhibit one or more of (i) disease stabilization, (ii) disease regression, (iii) improved lung function, and (iv) improvement of one or more symptoms of the cancer, any one or more of which may persist for at least 1 month, such as at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, or longer.

[0136]

[0118] The subject combination treatment disclosed herein can achieve such desired actions or outcomes, while synergistically providing one or more superior advantages including, but not limited to, (i) decreased amount (e.g., dosage regimen, number of doses, etc.) of one, more, or all of the therapeutic agents utilized in the combination therapy; (ii) avoiding, limiting, or reducing one or more undesirable side-effects associated with the use of any one of the plurality of different therapeutic agents when used in the therapeutically effective amount or clinically approved amount; and (iii) allowing for the use of an EGFR TKI that would otherwise be intolerable to the subject.

[0137]

[0119] Through the administration of a combination therapy disclosed herein, any of a range of undesirable sideeffects associated with amivantamab may be reduced, including rash, pruritus, dry skin, fatigue, edema, pyrexia, paronychia, pneumonia, musculoskeletal pain, dyspnea, cough, nausea, stomatitis, constipation, vomiting, diarrhea, abdominal pain, hemorrhage, decreased appetite, peripheral neuropathy, dizziness, and headache. In some embodiments, a side effect selected from back pain, bleeding gums, blistering, crusting, irritation, itching, or reddening of the skin, blood in the urine, bloody nose, burning, crawling, itching, numbness, painful, prickling, "pins and needles", or tingling feelings, chest pain or tightness, chills, cough, coughing or spitting up blood, cracked, dry, or scaly skin, dry, itching skin, fever, flushing, headache, loosening of the fingernails, muscle or bone pain, nausea and vomiting, nerve pain, rash with flat lesions or small raised lesions on the skin, redness or soreness around the fingernails, sneezing, swelling, trouble breathing, unsteadiness or awkwardness, and weakness in the arms, hands, legs, or feet is reduced. In some embodiments, diarrhea, rash, and / or nausea can be reduced. The combination treatment with a SOS1 inhibitor disclosed herein may allow administration of amivantamab when it would otherwise not be tolerable to the subject. The combination treatment with a subject SOS1 inhibitor may allow a more frequent dosage regimen of amivantamab that is otherwise too toxic or not tolerable to a subject in need of such treatment.

[0138]

[0120] The combination treatment as disclosed herein can utilize amivantamab at a therapeutically sub-optimal dose when used alone, but in combination with a SOS1 inhibitor disclosed herein yields overall therapeutic efficacy (e.g., promoting one or more desired therapeutic outcomes and / or reducing undesirable side-effects). In some embodiments, the combination therapy utilizes a dose of amivantamab less than that approved or recommended for treating a human subject for a given indication (e.g., a sub-therapeutic dose). In some embodiments, the sub- therapeutic dose is less than 95% of the approved dose of amivantamab, such as less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the approved dose of amivantamab. For example, a sub-therapeutic dose of amivantamab is less than the recommended dose of 1050 mg for patients less than 80 kg or less than the recommended dose of 1400 mg for patients greater than or equal to 80 kg. A sub-therapeutic dose of amivantamab may be less than 90% of the recommended dose of 1050 mg for patients less than 80 kg or less than 90% of the recommended dose of 1400 mg for patients greater than or equal to 80 kg, such as less than 945 mg for patients less than 80 kg or less than 1260 mg for patients greater than or equal to 80 kg. In some embodiments, amivantamab is administered at a dose of 1050 mg in combination with a SOS1 inhibitor disclosed herein. In some embodiments, amivantamab is administered at a dose of 1400 mg in combination with a SOS1 inhibitor disclosed herein. In some embodiments, amivantamab is administered at a dose of 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, or 1500 mg in combination with a SOS1 inhibitor disclosed herein.

[0139]

[0121] In practicing any of the subject methods, the SOS1 inhibitor may be administered at a dose of at least 5 mg daily, such as 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg daily in combination with amivantamab. In some embodiments, the SOS1 inhibitor is administered at a dose of 5 to 1000 mg, such as about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg in combination with amivantamab, such as in combination with 1050 mg or 1400 mg amivantamab. In some embodiments, the SOS1 inhibitor is administered once daily in an oral dosage form.

[0140]

[0122] In certain aspects, the present disclosure provides a method of treating cancer in a subject in need thereof. The method may comprise administering a pharmaceutical composition that comprises an effective amount of a small molecule SOS1 inhibitor to the subject, wherein said SOS1 inhibitor inhibits growth of a NSCLC cell line with an IC50 less than about 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM or even less, as ascertained in a growth inhibition assay utilizing the NSCLC cell line. In some embodiments, the SOS1 inhibitor inhibits an NSCLC cell line selected from the group consisting of Ba / F3-EGFR_Ex20_ASV insertion, Ba / F3-EGFR_L858R / T790M, PC9-EGFR Exl9 E746_A750 deletion, H1975-EGFR L858R / T790M, Ba / F3-EGFR-V769_D770insASV, Ba / F3-EGFR_D770_N771insNPH, H1993, LU0858, LU0387, LU3075, H3122, and H2228 with an IC50 less than about 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM or even less. In some embodiments, the S0S1 inhibitor inhibits growth of an NSCLC cell line with an IC50 at least 10, 50, or 100 times less than that of BI3406 or that of MRTX0902. In some embodiments, the SOS1 inhibitor synergistically inhibits growth of an NSCLC cell line in combination with amivantamab. In some embodiments, the SOS1 inhibitor is characterized in that it synergistically inhibits growth of NSCLC cells in combination with amivantamab to yield at least about 80% growth inhibition, when less than about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, or 5 nM of the SOS1 inhibitor is applied in combination with amivantamab applied at its IC50 molarity, in an in vitro growth inhibition assay using NSCLC cells. In some embodiments, the SOS1 inhibitor is characterized in that it synergistically increases percent of cell growth inhibition from about 10% to at least about 50%, when less than about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, or 5 nM of the SOS1 inhibitor is applied in combination with amivantamab applied at its IC10 molarity, as ascertained in an in vitro growth inhibition assay using NSCLC cells. In some embodiments, the SOS1 inhibitor is characterized in that it synergistically increases percent of cell growth inhibition from about 50% to at least about 80%, when less than about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, or 5 nM of the SOS1 inhibitor is applied in combination with amivantamab applied at its IC50 molarity, in an in vitro growth inhibition assay using NSCLC cells.

[0141]

[0123] In yet another aspect, the present disclosure provides a method of reducing proliferation of a cell comprising an EGFR mutation. The method may comprise administering to the cell (a) a small molecule SOS1 inhibitor disclosed herein, and (b) amivantamab, wherein the administration of (a) and (b) synergistically inhibits growth of NSCLC cells as evidenced by achieving a comparable or higher degree of growth inhibition when either (1) less than 90% of the SOS1 inhibitor is administered as compared to the amount required for the SOS1 inhibitor when administered alone; or (2) less than 90% of amivantamab is administered as compared to the amount required for amivantamab when administered alone. In some embodiments, amivantamab is administered in less than about 80%, 70%, 60%, 50%, 40%, 30%, 25%, 20%, 15%, or 10% of the amount required to achieve a comparable or higher degree of growth inhibition. In some embodiments, less than 1400 mg, such as less than 1350 mg, less than 1300 mg, less than 1250 mg, less than 1200 mg, less than 1150 mg, less than 1100 mg, less than 1050 mg, less than 1000 mg, less than 950 mg, less than 900 mg, less than 800 mg, less than 700 mg, less than 600 mg, less than 500 mg, less than 400 mg, or less than 350 mg of amivantamab is administered. In some embodiments, 1050 mg or 1400 mg amivantamab is administered.

[0142] Compounds

[0143]

[0124] A SOS1 inhibitor for use in the present disclosure can be any SOS1 inhibitor that is known in the art, and can include any entity that, upon administration to a subject, results in downregulation of SOS1 in the subject. For example, a suitable SOS1 inhibitor can be selected from a variety of types of molecules. In particular, the SOS1 inhibitor can be a biological or chemical compound, such as a simple or complex organic or inorganic molecule, peptide, peptido mimetic, protein (e.g., antibody), liposome, or a polynucleotide (e.g., small interfering RNA, short hairpin RNA, microRNA, antisense, aptamer, ribozyme, triple helix). In some embodiments, a method disclosed herein utilizes a small molecule SOS1 inhibitor. As used herein, the term “small molecule” refers to a low molecular weight organic compound, such as a compound having a molecular weight of less than 1500 g / mol, less than 1250 g / mol, less than 1000 g / mol, or less than 750 g / mol. Many compounds are known to inhibit SOS1 (e.g., compounds of WO 2005 / 097119, which is incorporated herein by reference in its entirety).

[0144]

[0125] In some embodiments, a small molecule SOS1 inhibitor may be conjugated to a degradation tag. A degradation tag may be configured to bind a degradation moiety having a capacity to degrade at least a portion of a target moiety that is bound by the degradation tag. In some embodiments, the target moiety is SOS1 or a substrate of SOS1.

[0145]

[0126] In some embodiments, a subject S0S1 inhibitor disrupts the interaction between SOS1 and KRAS at an IC50 of less than about 20 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.1 nM or even less, as ascertained utilizing the Ras-SOS interaction assay described in Example 3. In some embodiments, the SOS1 inhibitor is at least 5-times more potent than BI-3406, MRTX0902, BAY 293, RMC-5845, or BI-1701963, such as at least 10-times, 20-times, 30-times, 40-times, 50-times, 60-times, 70-times, 80-times, 90-times, or 100- times more potent, as ascertained utilizing the Ras-SOS interaction assay described in Example 3. In some embodiments, a subject SOS1 inhibitor inhibits growth of a cancer cell, such as an NSCLC cell line, with an IC50 less than about 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM or even less, as ascertained in a growth inhibition assay, optionally utilizing the NSCLC cell line. In some embodiments, the SOS1 inhibitor inhibits a NSCLC cell line selected from the group consisting of Ba / F3-EGFR_Ex20_ASV insertion, Ba / F3-EGFR_L858R / T790M, PC9-EGFR Exl9 E746_A750 deletion, H1975-EGFR L858R / T790M, Ba / F3-EGFR- V769_D770msASV, Ba / F3-EGFR_D770_N771insNPH, Hl 993, LU0858, LU0387, LU3075, H3122, and H2228 with an IC50 less than about 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM or even less. In some embodiments, the SOS1 inhibitor inhibits growth of a NSCLC cell line with an IC50 at least 10, 50, 100, 200, 300, 500, or 1000 times less than that of RMC-5845, BI-1701963, some embodiments, the SOS1 inhibitor inhibits growth of a NSCLC cell line with an IC50 at least 10, 50, 100, 200, 300, 500, or 1000 times less than that of a SOS inhibitor described in

[0146] W02021092115, WO2018172250, WO2019201848, WO2019122129, WO2018115380, WO2021127429, W02020180768, or W02020180770, each of which is herein incorporated by reference in its entirety for all purposes. In some embodiments, the SOS1 inhibitor synergistically inhibits growth of a cancer cell, such as an NSCLC cell line, in combination with amivantamab.

[0147]

[0127] In some embodiments, the SOS1 inhibitor is characterized in it synergistically inhibits growth of NSCLC cells in combination with amivantamab to yield at least about 80% growth inhibition when less than about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, or 5 nM of the SOS1 inhibitor is applied in combination with amivantamab applied at its IC50 molarity, in an in vitro growth inhibition assay using NSCLC cells. In some embodiments, the SOS1 inhibitor is characterized in that it synergistically increases percent of cell growth inhibition from about 10% to at least about 50%, when less than about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, or 5 nM of the SOS1 inhibitor is applied in combination with amivantamab applied at its IC10 molarity, as ascertained in an in vitro growth inhibition assay using NSCLC cells. In some embodiments, the SOS1 inhibitor is characterized in that it synergistically increases percent of cell growth inhibition from about 50% to at least about 80%, when less than about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, or 5 nM of the SOS1 inhibitor is applied in combination with amivantamab applied at its IC50 molarity, in an in vitro growth inhibition assay using NSCLC cells.

[0128] The compounds of Formula (I) disclosed herein—including the compounds of Formula (I-A), (I-B), (I-1),(I-B1), (I-B2), (I-C), (I-C1), (I-C2), (I-C3), (I-D), (I-D1), (I-D2), (I-E), (I-E1), (II-B), (II-C), and (III)—or a pharmaceutically acceptable salt or solvate thereof, are SOS modulators and have a wide range of applications in therapeutics, diagnostics, and other biomedical research.

[0129] In certain aspects, the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein: is selected from C5-7 carbocycle and 5- to 7-membered heterocycle, each of which is optionally substituted with one or more R11; is absent or selected from C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more R11a; L1is selected from a bond, C1-6 alkylene, and C1-6 haloalkylene; L2is selected from C5-25alkylene, C5-25alkenylene, C5-25alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is optionally substituted with one or more R11b, wherein L2is covalently bound to one of W3, W4, W5, W6, or W7; or L2is -L3-D-L4-, wherein L4is covalently bound to one of W3, W4, W5, W6, or W7; L3is selected from C1-10alkylene, C2-10alkenylene, C2-10alkynylene, 2- to 10-membered heteroalkylene, and 3- to 10-membered heteroalkenylene, each of which is optionally substituted with one or more R11b; D is absent or selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more R11d; L4is selected from C1-10alkylene, C2-10alkenylene, C2-10alkynylene, 2- to 10-membered heteroalkylene, and 3- to 10-membered heteroalkenylene, each of which is optionally substituted with one or more R11b; W2is selected from N(R2b), N, C(R2), C(R2)(R2a), and C(O); W3is selected from N(R3b), N, C(R3), C(R3)(R3a), and C(O); W4is selected from N(R4b), N, C(R4), C(R4)(R4a), and C(O); W5is selected from N(R5b), N, C(R5), C(R5)(R5a), and C(O); W6is selected from N(R6b), N, C(R6), C(R6)(R6a), and C(O); W7is selected from N(R7b), N, C(R7), C(R7)(R7a), and C(O); W8is selected from N(R8b), N, C(R8), C(R8)(R8a), and C(O); W9is selected from N, C(R9), and C; W10is selected from N, C(R10), and C; R1is C1-3alkyl optionally substituted with one or more R11c; R2, R2a, R3a, R4a, R5a, R6a, R7a, R8, and R8aare each independently selected from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), - C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20; R3, R4, R5, R6, and R7are each independently selected from a bond to L2, hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), - C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20; R2band R8bare each independently selected from hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -C(O)OR12, -OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), - CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20; R3b, R4b, R5b, R6b, and R7bare each independently selected from a bond to L2, hydrogen, -CN, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -C(O)OR12, - OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, - S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20; R9and R10are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle), wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) is independently optionally substituted with one, two, or three R20; R11, R11a, and R11dare each independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), -CH2N(R12)S(O)2(R13), and - P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R11bis independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), -CH2N(R12)S(O)2(R13), and - P(O)(R17)(R17a), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R11cis independently selected at each occurrence from halogen, -OR12, and -N(R12)(R13); R12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R13is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R12and R13, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycle optionally substituted with one, two, or three R20; R14is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl; R15is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R17and R17aare each independently selected at each occurrence from C1-6alkyl and C3-6cycloalkyl, wherein C1-6alkyl and C3-6cycloalkyl are optionally substituted with one, two or three R20; or R17and R17a, together with the phosphorous atom to which they are attached, form a 3- to 10-membered heterocycle; R20is independently selected at each occurrence from halogen, oxo, =NH, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, - S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, C1-6alkyl, C1-6haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, - N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; R21is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6 alkyl; R22is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6 alkyl; R23is independently selected at each occurrence from H and C1-6alkyl; R24is independently selected at each occurrence from H and C1-6alkyl; R25is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-10carbocycle, and 3- to 10-membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0130] In certain aspects, the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein: is selected from C5-7 carbocycle and 5- to 7-membered heterocycle, each of which is optionally substituted with one or more R11; is absent or selected from C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more R11a; L1is selected from a bond, C1-6 alkylene, and C1-6 haloalkylene; L2is selected from C5-25alkylene, C5-25alkenylene, C5-25alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is optionally substituted with one or more R11b, wherein L2is covalently bound to one of W3, W4, W5, W6, or W7; W2is selected from N(R2b), N, C(R2), C(R2)(R2a), and C(O); W3is selected from N(R3b), N, C(R3), C(R3)(R3a), and C(O); W4is selected from N(R4b), N, C(R4), C(R4)(R4a), and C(O); W5is selected from N(R5b), N, C(R5), C(R5)(R5a), and C(O); W6is selected from N(R6b), N, C(R6), C(R6)(R6a), and C(O); W7is selected from N(R7b), N, C(R7), C(R7)(R7a), and C(O); W8is selected from N(R8b), N, C(R8), C(R8)(R8a), and C(O); W9is selected from N, C(R9), and C; W10is selected from N, C(R10), and C; R1is C1-3alkyl optionally substituted with one or more R11c; R2, R2a, R3a, R4a, R5a, R6a, R7a, R8, and R8aare each independently selected from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), - C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20; R3, R4, R5, R6, and R7are each independently selected from a bond to L2, hydrogen, halogen, -CN, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), - C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20; R2band R8bare each independently selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -C(O)OR12, -OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), - CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein each C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-10carbocycle and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20; R3b, R4b, R5b, R6b, and R7bare each independently selected from a bond to L2, hydrogen, -CN, C1-6 alkyl, C2- 6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -C(O)OR12, - OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, - S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20; R9and R10are each independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle), wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, -CH2-(C3-10 carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) is independently optionally substituted with one, two, or three R20; R11and R11aare each independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), -CH2N(R12)S(O)2(R13), and - P(O)(R17)(R17a), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R11bis independently selected at each occurrence from halogen, oxo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), -CH2N(R12)S(O)2(R13), and - P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R11cis independently selected at each occurrence from halogen, -OR12, and -N(R12)(R13); R12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C0carbocycle, and 3- to 10-membered heterocycle, wherein C 6alkyl, C2-6alkenyl, C2-6alkynyl, C 0carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or R12and R13, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycle optionally substituted with one, two, or three R20; R14is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl; R15is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C carbocycle, and 3- to 10-membered heterocycle, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R17and R17aare each independently selected at each occurrence from C1-6alkyl and C3-6cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one, two or three R20; or R17and R17a, together with the phosphorous atom to which they are attached, form a 3- to 10-membered heterocycle; R20is independently selected at each occurrence from halogen, oxo, =NH, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C0carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, - S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, - N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; R21is independently selected at each occurrence from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; R22is independently selected at each occurrence from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; R23is independently selected at each occurrence from H and C1-6 alkyl; R24is independently selected at each occurrence from H and C1-6 alkyl; R25is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-10 carbocycle, and 3- to 10-membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0131] In some embodiments, the compound of Formula (I) is a compound of Formula (I-A): or a pharmaceutically acceptable salt or solvate thereof.

[0132] In some embodiments, the compound of Formula (I-A) is a compound selected from:

[0133] In some embodiments, the compound of Formula (I) is a compound of Formula (I-B), such as a compoundof Formula (I-B1) or (I-B2):

[0148] or a pharmaceutically acceptable salt or solvate thereof.

[0134] In some embodiments, the compound of Formula (I-B) is a compound selected from: .

[0135] In some embodiments, the compound of Formula (I) is a compound of Formula (I-C), such as a compoundof Formula (I-C1), (I-C2), or (I-C3):

[0149] or a pharmaceutically acceptable salt or solvate thereof.

[0136] In some embodiments, the compound of Formula (I-C) is a compound selected from: .

[0137] In some embodiments, the compound of Formula (I) is a compound of Formula (I-D), such as a compoundof Formula (I-D1) or (I-D2): or a pharmaceutically acceptable salt or solvate thereof.

[0138] In some embodiments, the compound of Formula (I-D) is a compound selected from:

[0139] In some embodiments, the compound of Formula (I) is a compound of Formula (I-E), such as a compoundof Formula (I-E1):

[0150] or a pharmaceutically acceptable salt or solvate thereof.

[0140] In some embodiments, the compound of Formula (I-E) is a compound selected from: .

[0141] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), W2 is N. In someembodiments, W3is selected from N(R3b), N, C(R3), and C(O), such as NCH3, N, CH, CCH3, and C(O). In some embodiments, W3is selected from C(R3) and C(O), such as CH, CCH3and C(O). In some embodiments, W3is CH. In some embodiments, W3is CCH3. In some embodiments, W4is selected from N(R4b), N, C(R4), and C(O), such as N(R4b), N, C(R4), and C(O), wherein R4band R4are each independently a bond to L2. In some embodiments, W4is selected from N(R4b) and N, such as N(R4b), wherein R4bis a bond to L2. In some embodiments, W4is N. In some embodiments, W5is selected from N(R5b), N, C(R5), and C(O), such as N(R5b), NCH3, N, CH, C(R5), and C(O), wherein R5band R5are each independently a bond to L2. In some embodiments, W5is selected from N(R5b), N, and C(R5), such as N(R5b), NCH3, N, CH, and C(R5), wherein R5band R5are each independently a bond to L2. In some embodiments, W5is selected from N(R5b) and C(R5), such as N(R5b), NCH3, and CH, wherein R5bis a bond to L2. In some embodiments, W5is N(R5b). In some embodiments, W6is selected from C(R6) and C(O), such as COCH3, CH, C(R6), and C(O), wherein R6is a bond to L2. In some embodiments, W6is C(O). In some embodiments, W7is C(R7), such as W7is C(R7) wherein R7is a bond to L2. In some embodiments, W7is C(R7), wherein R7is not hydrogen, such as R7is selected from C3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and -OR12, wherein C3-10 cycloalkyl and 3- to 10-membered heterocycloalkyl are optionally substituted with one, two, or three R20. In some embodiments, W8is C(R8), such as W8is CH. In some embodiments, W9is C. In some embodiments, W10is C.

[0142] In some embodiments, for a compound of Formula (I), (I-A), (I-C), (I-D), or (I-E), W2 is N; W3 is N(R3b);W4is C(O); and W9and W10are each C, such as W2is N; W3is NCH3; W4is C(O); and W9and W10are each C. In some embodiments, for a compound of Formula (I), (I-B), (I-C), (I-D), or (I-E),W2is N; W3is C(O); W4is N(R4b); and W9and W10are each C, such as W2is N; W3is C(O); W4is N(R4b), wherein R4bis a bond to L2; and W9and W10are each C. In some embodiments, for a compound of Formula (I), (I-A), (I-C), (I-D), or (I-E), W2is N; W3is C(R3); W4is N; and W9and W10are each C, such as W2is N; W3is CH or CCH3; W4is N; and W9and W10are each C. In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), W5is C(R5); W6is C(R6); W7is C(R7); W8is C(R8); and W9and W10are each C, such as W5is CH or C(R5), wherein R5is a bond to L2; W6is CH or C(R6), wherein R6is a bond to L2; W7is C(R7); W8is CH; and W9and W10are each C. In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-C), or (I-E), W5is N(R5b); W6is C(O); W7is C(R7); W8is C(R8); and W9and W10are each C, such as W5is NCH3or N(R5b), wherein R5bis a bond to L2; W6is C(O); W7is C(R7); W8is CH; and W9and W10are each C. In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-D), or (I-E), W5is N; W6is C(R6); W7is C(R7); W8is C(R8); and W9and W10are each C, such as W5is N; W6is COCH3, CH, or C(R6), wherein R6is a bond to L2; W7is C(R7); W8is CH; and W9and W10are each C. In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), W2is N; W3is selected from N(R3b), N, C(R3), and C(O); W4is selected from N(R4b), N, C(R4), and C(O); W5is selected from N(R5b), N, and C(R5); W6is selected from C(R6) and C(O); W7is C(R7); W8is C(R8); and W9and W10are each C, such as W2is N; W3is selected from NCH3, N, CH, CCH3, and C(O); W4is selected from N(R4b), N, C(R4), and C(O), wherein R4band R4are each independently a bond to L2; W5is selected from N(R5b), NCH3, N, CH, and C(R5), wherein R5band R5are each independently a bond to L2; W6is selected from COCH3, CH, C(R6), and C(O), wherein R6is a bond to L2; W7is C(R7); W8is CH; and W9and W10are each C. In some embodiments, for a compound of Formula (I), (I- A), (I-B), (I-C), (I-D), or (I-E), W2is N; W3is selected from C(R3) and C(O); W4is selected from N(R4b) and N; W5is selected from N(R5b) and C(R5); W6is selected from C(R6) and C(O); W7is C(R7); W8is CH; and W9and W10are each C, such as W2is N; W3is selected from CH, CCH3, and C(O); W4is selected from N(R4b) and N, wherein R4bis a bond to L2; W5is selected from N(R5b), NCH3, CH, and C(R5), wherein R5band R5are each independently a bond to L2; W6is selected from COCH3, CH, C(R6), and C(O), wherein R6is a bond to L2; W7is C(R7); W8is CH; and W9and W10are each C.

[0151] .

[0144] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), R2, R2a, R3a, R4a,R5a, R6a, R7a, R8, and R8aare each independently selected from hydrogen, halogen, -CN, C1-3 alkyl, C1-3 haloalkyl, - OH, -NH2, -NHCH3, and -N(CH3)2. In some embodiments, R2, R2a, R3a, R4a, R5a, R6a, R7a, R8, and R8aare each independently selected from hydrogen and -CH3, such as hydrogen.

[0145] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), R3, R4, R5, and R6 are each independently selected from a bond to L2, hydrogen, halogen, -CN, C1-6 alkyl, C3-6 carbocycle, 3- to 6- membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), - N(R14)C(O)R15, -S(O)2R15, and -S(O)2N(R12)(R13), wherein each C1-6alkyl, C3-6carbocycle, and 3- to 6-membered heterocycle is independently optionally substituted with one, two, or three R20; and R7is selected from a bond to L2, C1-6 alkyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -N(R12)(R13), -C(O)R15, -C(O)N(R12)(R13), - S(O)2R15, and -SO2N(R12)(R13), wherein C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20. In some embodiments, R3, R4, R5, and R6are each independently selected from a bond to L2, hydrogen, halogen, -CN, C1-3alkyl, C1-3haloalkyl, -OH, -OCH3, -NH2, -NHCH3, - N(CH3)2; and R7is selected from a bond to L2, C1-6 alkyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, - N(R12)(R13), -C(O)R15, -C(O)N(R12)(R13), -S(O)2R15, and -SO2N(R12)(R13), wherein C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20. In some embodiments, R3, R4, R5, and R6are each independently selected from a bond to L2, hydrogen, -CH3, and -OCH3; and R7is selected from a bond to L2, C1-6 alkyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -N(R12)(R13), -C(O)R15, - C(O)N(R12)(R13), -S(O)2R15, and -SO2N(R12)(R13), wherein C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20.

[0146] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-C), (I-D), or (I-E), R2b and R8b areeach independently selected from hydrogen and C1-3 alkyl, such as hydrogen and -CH3. In some embodiments, R3b, R4b, R5b, R6b, and R7bare each independently selected from a bond to L2, hydrogen, and C1-3 alkyl, such as a bond to L2, hydrogen, and -CH3. In some embodiments, R3b, R4b, R5b, R6b, and R7bare each independently selected from a bond to L2and -CH3. In some embodiments, R3b, R4b, R5b, R6b, and R7bare each independently selected from a bond to L2. In some embodiments, R9and R10are each hydrogen.

[0147] For a compound of Formula (I) wherein L2 is -L3-D-L4-, it is understood that the selection of “a bond to L2”for one of R3, R4, R5, R6, R7,R3b, R4b, R5b, R6b, or R7binherently includes a bond to -L3-D-L4-, specifically to L4. For the avoidance of doubt, any recitation of R3, R4, R5, R6, R7,R3b, R4b, R5b, R6b, and / or R7bthat includes “a bond to L2” also may be considered to include “a bond to L4”.

[0148] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-B1), (I-B2), (I-C), (I-C1), (I-C2), (I-C3), (I-D), (I-D1), (I-D2), (I-E), or (I-E1), R1is selected from C1-3alkyl and C1-3haloalkyl, such as -CH3, -CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, CH2CH2F, -CH2CHF2, and -CH2CF3. In some embodiments, R1is selected from C1-3 alkyl, such as -CH3 and -CH2CH3. In some embodiments, R1is -CH3. In some embodiments, R1is (R)-CH3. In some embodiments, R1is (S)-CH3.

[0149] In some embodiments, for a compound of Formula (I), (I-B), (I-C), (I-C1), (I-C3), (I-D), (I-D1), (I-D2), (I-E), or (I-E1), R3is selected from hydrogen, halogen, -CN, C1-6alkyl, C3-6carbocycle, 3- to 6-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -N(R14)C(O)R15, - S(O)2R15, and -S(O)2N(R12)(R13), wherein each C1-6 alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle is independently optionally substituted with one, two, or three R20. In some embodiments, R3is selected from hydrogen, halogen, -CN, C1-3alkyl, C1-3haloalkyl, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2. In some embodiments, R3is selected from hydrogen, halogen, -CN, -OR12, and C1-6 alkyl optionally substituted with one, two, or three R20. In some embodiments, R3is C1-6 alkyl optionally substituted with one, two, or three R20. In some embodiments, R3is hydrogen or -CH3. In some embodiments, R3is hydrogen. In some embodiments, R3is -CH3.

[0150] In some embodiments, for a compound of Formula (I), (I-B), (I-C), (I-C2), (I-D), or (I-E), R3b is selectedfrom hydrogen and C1-3 alkyl, such as hydrogen and -CH3. In some embodiments, R3bis -CH3. In some embodiments, R3bis hydrogen.

[0151] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-B2), (I-D), (I-D2), (I-E), or (I-E1),R5is selected from hydrogen, halogen, -CN, C1-6alkyl, C3-6carbocycle, 3- to 6-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, and - S(O)2N(R12)(R13), wherein each C1-6 alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle is independently optionally substituted with one, two, or three R20. In some embodiments, R5is selected from hydrogen, halogen, - CN, C1-3alkyl, C1-3haloalkyl, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2. In some embodiments, R5is selected from hydrogen, -OR12, and C1-6alkyl optionally substituted with one, two, or three R20. In some embodiments, R5is hydrogen or -CH3. In some embodiments, R5is hydrogen. In some embodiments, R5is -CH3.

[0152] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-B1), (I-D), or (I-E), R5b is selectedfrom hydrogen and C1-3alkyl, such as hydrogen and -CH3. In some embodiments, R5bis selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three R20. In some embodiments, R5bis -CH3. In some embodiments, R5bis hydrogen. In some embodiments, R5bis a bond to L2.

[0153] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-B2), (I-C), (I-C3), (I-E), or (I-E1), R6is selected from hydrogen, halogen, -CN, C1-6alkyl, C3-6carbocycle, 3- to 6-membered heterocycle, -OR12, -SR12, - N(R12)(R13), -C(O)OR12, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, and - S(O)2N(R12)(R13), wherein each C1-6 alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle is independently optionally substituted with one, two, or three R20. In some embodiments, R6is selected from hydrogen, halogen, - CN, C1-3alkyl, C1-3haloalkyl, -OH, -OCH3, -NH2, -NHCH3, and -N(CH3)2. In some embodiments, R6is selected from hydrogen, -OR12, and C1-6alkyl optionally substituted with one, two, or three R20, and wherein R12is selected from C1-6 alkyl. In some embodiments, R6is selected from hydrogen and -OCH3. In some embodiments, R6is hydrogen. In some embodiments, R6is -OCH3.

[0154] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-B1), (I-B2), (I-C), (I-C1), (I-C2), (I-C3), (I-D), (I-D1), or (I-D2), R7is selected from C1-6alkyl, C3-10carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)R15, -C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein each C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20. In some embodiments, R7is selected from C1-6alkyl, C3-10carbocycle, 3- to 10-membered heterocycle, -OR12, - N(R12)(R13), -C(O)R15, -C(O)N(R12)(R13), -S(O)2R15, and -SO2N(R12)(R13), wherein C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20. In some embodiments, R7is selected from C1-6alkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, and -N(R12)(R13), wherein C1-6alkyl, C3-10cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one, two, or three R20. In some embodiments, R7is 3- to 10-membered heterocycloalkyl optionally substituted with one, two, or three R20, such as R7is 4- to 6-membered heterocycloalkyl optionally substituted with one, two, or three R20. In some embodiments, R7is 3- to 10-membered heterocycloalkyl optionally substituted with one, two, or three R20, wherein the heterocycloalkyl comprises at least one O, N, or S, such as one O atom, one or two N atoms, or one S atom. In some embodiments, R7is 3- to 6-membered heterocycloalkyl optionally substituted with one, two, or three R20, wherein the heterocycloalkyl comprises S(O)2. In some embodiments, R7is C3-10 cycloalkyl optionally substituted with one, two, or three R20, such as R7is C3-6cycloalkyl optionally substituted with one, two, or three R20. In some embodiments, R7is C3-4cycloalkyl optionally substituted with one R20, optionally wherein R20is -CN. In some embodiments, R7is C1-6 alkyl optionally substituted with one, two, or three R20, such as R7is C1-6 alkyl substituted with one or two R20. In some embodiments, R7is -N(R12)(R13). In some embodiments, R7is -OR12, such as -O(3- to 6-membered heterocycloalkyl). In some embodiments, R7is substituted with at least one -CN. In some embodiments, R7is unsubstituted. In some embodiments, R7is selected from C3-10carbocycle and 3- to 10- membered heterocycle, each of which is optionally substituted with one, two, or three R20. In some embodiments, R7is selected from C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one, two, or three substituents selected from oxo, -CN, and C1-6 alkyl. In some embodiments, R7is 4- to 6-membered heterocycloalkyl substituted with one, two, or three substituents selected from oxo, -CN, and C1-3alkyl. In some embodiments, R7is C3-4cycloalkyl substituted with one, two, or three substituents selected from oxo, -CN, and C1-3alkyl.

[0155] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-B1), (I-B2), (I-C), (I-C1), (I-C2), (I-C3), (I-D), (I-D1), or (I-D2), R7is selected from C1-6alkyl, C3-10carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)R15, -C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)(NR12)R15, -S(O)2N(R12)(R13), - CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)(NR12)R15, and -CH2S(O)2N(R12)(R13), wherein each C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20. In some embodiments, R7is selected from C1-6alkyl, C3-10carbocycle, 3- to 10-membered heterocycle, -OR12, -N(R12)(R13), -C(O)R15, -C(O)N(R12)(R13), -S(O)2R15, -S(O)(NR12)R15, and -SO2N(R12)(R13), wherein C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20. In some embodiments, R7is 3- to 6-membered heterocycloalkyl optionally substituted with one, two, or three R20, wherein the heterocycloalkyl comprises S(O)(NR12).

[0156] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-B1), (I-B2), (I-C), (I-C1), (I-C2), (I- , wherein: n1 is an integer from 1 to 3; n2 is an integer from 0 to 2; n3 is an integer from 0 to 2; n4 is 0 or 1; and X is selected from -O-, -S(O2)-, -P(O)-, -CH2-, -CH(OH)-, -CH(OR12)-, -CH(R20)-, -C(R20)2-, -NR12-, - CH(N(R12)(R13))-, -CH(C(O)N(R12)(R13))-, and -CH(S(O)2N(R12)(R13))-, wherein R12, R13, and R20are as defined elsewhere herein, and optionally wherein two R20groups, or R20and R12, join together with the atom(s) to which they are attached to form a ring. For example, R7may be selected from some embodiments, X is selected from -O-, -S(O)2-, - S(O)(NR12)-, -P(O)-, -CH2-, -CH(OH)-, -CH(OR12)-, -CH(R20)-, -C(R20)2-, -NR12-, -CH(N(R12)(R13))-, - CH(C(O)N(R12)(R13))-, and -CH(S(O)2N(R12)(R13))-.

[0152]

[0157] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-Bl), (I-B2), (I-C), (I-Cl), (I-C2), (I-

[0153]

[0154] Of . In some embodiments, R7is selected from ' — f 0 , and . , In some embodiments, R7is In some embodiments, , In some embodiments, R7is ,P

[0155] --N N — — N N-S=O embodiments, R7is — f . In some embodiments, R7is ' In some embodiments, R7is . , In some embodiments, R7is

[0156]

[0158] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-Bl), (I-B2), (I-C), (I-Cl), (I-C2), (I- C3), (I-D), (I-Dl), (I-D2), (I-E), or (I-El), R8is selected from hydrogen, halogen, and Ci-6 alkyl optionally substituted with one, two, or three R20. In some embodiments, R8is hydrogen.

[0157]

[0159] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-Bl), (I-B2), (I-C), (I-Cl), (I-C2), (I-

[0158] C3), (I-D), (I-Dl), (I-D2), (I-E), or (I-El), is selected from C3-10 carbocycle and 3- to 10-membered heterocycle, such as C5.7 carbocycle and 5- to 7-membered heterocycle, each of which is optionally substituted with one or more R11. In some embodiments, is selected from C5.7 cycloalkyl, 5- to 7-membered heterocycloalkyl, 5- to 7-membered heteroaryl, and phenyl, each of which is optionally substituted with one or more

[0159] R11. In some embodiments, is selected from phenyl, pyridyl, and thiophenyl, each of which is optionally substituted with one or more R11. In some embodiments, is selected from embodiments, R11, when present, is independently selected at each occurrence from fluorine and -CH3. In some

[0160]

[0160] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-Bl), (I-B2), (I-C), (I-Cl), (I-C2), (I- C3), (I-D), (I-Dl), (I-D2), (I-E), or (I-El), L1is selected from Ci-6 alkylene and Ci-6 haloalkylene, such as C1.3 alkylene and C1.3 haloalkylene. In some embodiments, L1is selected from a bond and C1.3 haloalkylene. In some embodiments, L1is C1.3 haloalkylene, such as -CF2-, -CF2CH2-, or -CF2CH2CH2-. In some embodiments, L1is C1.2 haloalkylene, such as -CF2- or -CF2CH2-. In some embodiments, L1is -CF2-. In some embodiments, L1is -CF2CH2-. In some embodiments, L1is -CF2CH2CH2-. In some embodiments, L1is a bond. In some embodiments, L1is selected from a bond, -O-, -NR12-, -S-, Ci-6 alkylene, Ci-6 haloalkylene, and 2- to 6-membered heteroalkylene, wherein Ci-6 alkylene, Ci-e haloalkylene, and 2- to 6-membered hetero alkylene are optionally substituted with one or more Rllb. In some embodiments, L1is selected from -O-, -NR12-, -S-, and 2- to 6-membered heteroalkylene, wherein 2- to 6-membered heteroalkylene is optionally substituted with one or more Rllb. In some embodiments, L1is Ci-6 alkylene optionally substituted with one or more Rl lb, such as one, two, or three Rllb. In some embodiments, L1is selected from a bond, -O-, -NR12-, -S-, C1.3 alkylene, C1.3 haloalkylene, and 2- to 3-membered heteroalkylene, wherein C1.3 alkylene, C1.3 haloalkylene, and 2- to 3-membered hetero alkylene are optionally substituted with one or more Rllb. In some embodiments, L1is selected from -O-, -NR12-, -S-, and 2- to 3-membered heteroalkylene, wherein 2- to 3-membered heteroalkylene is optionally substituted with one or more Rllb. In some embodiments, L1is C1.3 alkylene substituted with one or more Rllb, such as one, two, or three Rl lb.

[0161]

[0161] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-Bl), (I-B2), (I-C), (I-Cl), (I-C2), (I-

[0162] C3), (I-D), (I-Dl), (I-D2), (I-E), or (I-El), is absent or selected from C4.8 carbocycle and 4- to 8-membered heterocycle, each of which is optionally substituted with one or more Rl la. In some embodiments, is absent or selected from phenyl and 4- to 8-membered heterocycle, each of which is optionally substituted with one or more

[0163] Rlla. In some embodiments, optionally substituted with one or more Rl la. In some embodiments, is absent or selected from phenyl, azetidine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more Rl la. In some embodiments, is selected from phenyl, azetidine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more Rl la. In some embodiments, is selected from azetidine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more -CH3. In some embodiments, phenyl, optionally substituted with one or more Rl la. In some embodiments, , optionally substituted with one or more Rl la. In some embodiments, azetidine, optionally substituted with one or more Rl la. In some embodiments, , optionally substituted with one or more Rl la. In some embodiments, pyrrolidine, optionally substituted with one or more Rl la. In some embodiments, is piperidine, optionally substituted with one or more Rl la. In some embodiments, , optionally substituted with one or more Rlla. In some embodiments, . In some embodiments, is unsubstituted. In some embodiments, is substituted with one or more Rl la, such as one, two or three Rl la. In some embodiments,

[0164] Rllais independently selected at each occurrence from halogen, -CN, Ci-6 alkyl, C3.6 carbocycle, 3- to 6-membered heterocycle, -OR12, -N(R12)(R13), -N(R14)S(O)2R15, -C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, and - S(O)2N(R12)(R13), wherein Ci-6 alkyl, C3.6 carbocycle, and 3- to 6-membered heterocycle are optionally substituted with one, two, or three R20. In some embodiments, Rl lais independently selected at each occurrence from halogen, Ci-6 alkyl, and Ci-e haloalkyl. In some embodiments, Rl lais independently selected at each occurrence from Ci-6 alkyl. In some embodiments, Rllais -CH3.

[0165]

[0162] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-Bl), (I-B2), (I-C), (I-Cl), (I-C2), (I- C3), (I-D), (I-Dl), (I-D2), (I-E), or (I-El), L2is selected from Cs.25 alkylene, Cs.25 alkenylene, Cs.25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is optionally substituted with one or more Rl lb. In some embodiments, L2is selected from Cs.25 alkylene, Cs.25 alkenylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is optionally substituted with one or more Rllb. In some embodiments, L2, together with the atoms to which it is attached, forms a 16- to 36-membered macrocyclic ring, such as a 16- to 24-membered macrocyclic ring. In some embodiments, L2is selected from Ce-is alkylene, Ce-is alkenylene, Ce-is alkynylene, 6- to 15-membered heteroalkylene, and 6- to 15-membered heteroalkenylene, each of which is optionally substituted with one or more Rl lb. In some embodiments, L2is selected from C5-10 alkylene, C5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10-membered heteroalkenylene, each of which is optionally substituted with one or more Rl lb. In some embodiments, an alkenylene or hetero alkenylene of L2comprises one carbon-carbon double bond. In some embodiments, a hetero alkylene or heteroalkenylene of L2comprises at least one oxygen or nitrogen atom. In some embodiments, a hetero alkylene or heteroalkenylene of L2comprises at least one basic nitrogen. In some embodiments, L2is selected from C5.9 alkylene, C5.9 alkenylene, and 5- to 9-membered heteroalkylene, each of which is optionally substituted with one or more Rllb. In some embodiments, L2is selected from Ce-9 alkylene, Ce-9 alkenylene, and 6- to 9- membered heteroalkylene, each of which is optionally substituted with one or more Rllb. In some embodiments, L2is selected from C5.8 alkylene, C5.8 alkenylene, and 5- to 8-membered heteroalkylene, each of which is optionally substituted with one or more Rl lb. In some embodiments, L2is selected from Ce-s alkylene, Ce-s alkenylene, and 6- to 8-membered heteroalkylene, each of which is optionally substituted with one or more Rl lb. In some embodiments, L2is selected from Ce-s alkylene and Ce-s alkenylene, each of which is optionally substituted with one or more Rl lb. In some embodiments, L2is selected from Ce alkylene and Ce alkenylene, each of which is optionally substituted with one or more Rllb. In some embodiments, L2is selected from C7 alkylene and C7 alkenylene, each of which is optionally substituted with one or more Rl lb. In some embodiments, L2is selected from Cs alkylene and Cs alkenylene, each of which is optionally substituted with one or more Rllb. In some embodiments, L2is - CH2CHCH(CH2)4-. In some embodiments, L2is 6- to 8-membered heteroalkylene, optionally substituted with one or more Rllb. In some embodiments, L2is 6-membered hetero alkylene, optionally substituted with one or more Rl lb. In some embodiments, L2is 7-membered heteroalkylene, optionally substituted with one or more Rl lb. In some embodiments, L2is 8-membered hetero alkylene, optionally substituted with one or more Rl lb. In some embodiments, L2is 8-membered hetero alkylene, wherein the heteroalkylene comprises one oxygen atom. In some embodiments, L2is -(CH2)2-sO(CH2)o-5-, such as L2is -(CH2)2-sO(CH2)2-5-- In some embodiments, L2is - (CH2)4O(CH2)3-. In some embodiments, Rl lbis independently selected at each occurrence from halogen, oxo, Ci-e alkyl, Ci-e haloalkyl, (Ci-6 alkyl)-OH, and -OH. In some embodiments, Rllbis independently selected at each occurrence from -F, =0, -CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2OH, and -OH. In some embodiments, Rl lbis independently selected at each occurrence from -CH3, -CH2OH, -CH2F, -CHF2, and -CF3, or two Rl lbjoin to form =0 or C3.e cycloalkyl, such as cyclopropyl. In some embodiments, Rl lbis independently selected at each occurrence from -CH3, -CH2OH, -CH2F, -CHF2, and -CF3, or two Rllbjoin to form C3.e cycloalkyl, such as cyclopropyl. In some embodiments, Rllbis independently selected at each occurrence from -CH3, -F, -CN, and -OH. In some embodiments, L2comprises -C(O)N(R14)- or -N(R14)C(O)-. In some embodiments, L2comprises - 0-. In some embodiments, L2is substituted with at least one -CH3, -CH2OH, -CH2F, -CHF2, or -CF3, or two substituents join to form cyclopropyl. In some embodiments, L2is substituted with at least one -CH3, -F, -CN, or - OH. In some embodiments, L2is unsubstituted.

[0166]

[0163] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-Bl), (I-B2), (I-C), (I-Cl), (I-C2), (I- C3), (I-D), (I-Dl), (I-D2), (I-E), or (I-El), L2is -(C1.5 alkylene)-C(O)N(R14)-(Ci.5alkylene)-, such as -(C1.5 alkylene)-C(O)N(CH3)-(Ci-5 alkylene)- or -(C1.5 alkylene)-C(0)NH-(Ci-5 alkylene)-, wherein C1.5 alkylene is optionally substituted with one or more Rl lb. In some embodiments, L2is -(C1.2 alkylene)-C(O)N(R14)-(C3.4 alkylene)-, such as -(C1.2 alkylene)-C(O)N(CH3)-(C3.4 alkylene)- or -(C1.2 alkylene)-C(O)NH-(C3.4 alkylene)-, wherein C1.2 alkylene and C3.4 alkylene are each independently optionally substituted with one or more Rllb. In some embodiments, Rl lbis independently selected at each occurrence from halogen, Ci-6 alkyl, Ci-6 haloalkyl, (Ci-6 alkyl)-OH, and -OH. In some embodiments, Rllbis independently selected at each occurrence from -F, -CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2OH, and -OH. In some embodiments, Rl lbis independently selected at each occurrence from -CH3, -CH2OH, -CH2F, -CHF2, and -CF3, or two Rl lbjoin to form C3.e cycloalkyl, such as cyclopropyl. In some embodiments, Rllbis independently selected at each occurrence from -CH3, -F, -CN, and -OH. In some embodiments, L2is substituted with at least one -CH3, -F, -CN, or -OH.

[0167]

[0164] In some embodiments, L2is selected from -C(Rllb)(Rl lb)-(C3.io alkylene)-C(Rl lb)(Rl lb)-, -CH(Rl lb)-(C3.io alkylene)-C(Rllb)(Rl lb)-, -CH2-(C3-io alkylene)-C(Rl lb)(Rl lb)-, -CH(Rllb)-(C3.io alkylene)-CH(Rllb)-, -CH2-(C3-io alkylene)-CH(Rllb)-, -C(Rl lb)(Rllb)-(C3.io alkenylene)-C(Rllb)(Rllb)-, -CH(Rllb)-(C3.io alkenylene)-C(Rl lb)(Rllb)-, - CH2-(C3.IO alkenylene)-C(Rl lb)(Rl lb)-, -CH(Rllb)-(C3.io alkenylene)-CH(Rl lb)-, -CH2-(C3.IO alkenylene)-CH(Rl lb)-, - C(Rllb)(Rllb)-(3- to 10-membered heteroalkylene)-C(Rl lb)(Rl lb)-, -CH(Rllb)-( 3- to 10-membered hetero alkylene) - C(Rllb)(Rllb)-, -CH2-(3- to 10-membered heteroalkylene)-C(Rllb)(Rl lb)-, -CH(Rllb)-( 3- to 10-membered heteroalky lene)-CH(Rllb)-, -CH2-(3- to 10-membered heteroalkylene)-CH(Rllb)-, -C(Rl lb)(Rllb)-(3- to 10-membered heteroalkenylene)-C(Rl lb)(Rllb)-, -CH(Rl lb)-(3- to 10-membered heteroalkenylene)-C(Rllb)(Rllb)-, -CH2-(3- to 10- membered heteroalkenylene)-C(Rllb)(Rllb)-, -CH(Rl lb)-(3- to 10-membered heteroalkenylene)-CH(Rllb)-, and - CH2-(3- to 10-membered heteroalkenylene)-CH(Rl lb)-. In some embodiments, L2is selected from -C(Rllb)(Rllb)- (C3.io alkylene)-C(Rllb)(Rl lb)-, -CH(Rllb)-(C3.io alkylene)-C(Rllb)(Rl lb)-, -CH2-(C3.IO alkylene)-C(Rllb)(Rl lb)-, - CH(Rllb)-(C3.io alkylene)-CH(Rl lb)-, and -CH2-(C3.io alkylene)-CH(Rllb)-. In some embodiments, L2is selected from -C(Rl lb)(Rllb)-(C3.io alkenylene)-C(Rllb)(Rllb)-, -CH(Rllb)-(C3.io alkenylene)-C(Rllb)(Rllb)-, -CH2-(C3.IO alkenylene)-C(Rllb)(Rl lb)-, -CH(Rllb)-(C3.io alkenylene)-CH(Rllb)-, and -CH2-(C3.IO alkenylene)-CH(Rl lb)-. In some embodiments, L2is selected from -C(Rllb)(Rl lb)-(3- to 10-membered heteroalkylene)-C(Rl lb)(Rllb)-, -CH(Rl lb)-( 3- to 10-membered heteroalky lene)-C(Rl lb)(Rl lb)-, -CH2-(3- to 10-membered heteroalkylene)-C(Rllb)(Rllb)-, - CH(Rllb)-( 3- to 10-membered heteroalky lene)-CH(Rl lb)-, and -CH2-(3- to 10-membered heteroalky lene)-CH(Rl lb)-. In some embodiments, L2is selected from -C(Rllb)(Rl lb)-(3- to 10-membered heteroalkenylene)-C(Rl lb)(Rllb)-, - CH(Rllb)-(3- to 10-membered heteroalkenylene)-C(Rllb)(Rl lb)-, -CH2-(3- to 10-membered heteroalkenylene)- C(Rllb)(Rllb)-, -CH(Rl lb)-(3- to 10-membered heteroalkenylene)-CH(Rllb)-, and -CH2-(3- to 10-membered heteroalkenylene)-CH(Rllb)-. Any C3 -10 alkylene, C3-10 alkenylene, 3- to 10-membered heteroalkylene, or 3- to 10- membered heteroalkenylene in this paragraph may optionally be substituted with one or more Rl lb. In some embodiments, Rl lbis independently selected at each occurrence from halogen, oxo, Ci-6 alkyl, Ci-6 haloalky 1, (Ci-6 alkyl)-OH, and -OH. In some embodiments, Rllbis independently selected at each occurrence from -F, -CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2OH, and -OH. In some embodiments, Rl lbis independently selected at each occurrence from -CH3, -CH2OH, -CH2F, -CHF2, and -CF3, or two Rl lbjoin to form =0 or C3.6 cycloalkyl, such as cyclopropyl.

[0168]

[0165] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-Bl), (I-B2), (I-C), (I-Cl), (I-C2), (I- C3), (I-D), (I-Dl), (I-D2), (I-E), or (I-El), L2is -L3-D-L4-, wherein L3is selected from Cnio alkylene, C2-10 alkenylene, C2-10 alkynylene, 2- to 10-membered heteroalkylene, and 3- to 10-membered heteroalkenylene, each of which is optionally substituted with one or more Rl lb; D is absent or selected from C3-12 carbocycle and 3- to 12- membered heterocycle, each of which is optionally substituted with one or more Rlld; and L4is selected from Cnio alkylene, C2-10 alkenylene, C2-10 alkynylene, 2- to 10-membered heteroalkylene, and 3- to 10-membered heteroalkenylene, each of which is optionally substituted with one or more Rl lb. As noted above, alkenylene and alkynylene groups comprise one or more carbon-carbon double or triple bonds, respectively (i.e., comprising two or more carbon atoms, for example as in C2-10 alkenylene, C2-10 alkynylene, C2-8 alkenylene, C2-8 alkynylene, C5.25 alkenylene, C5.25 alkynylene, Ce-is alkenylene, Ce-is alkynylene, C5-10 alkenylene, and C5-10 alkynylene). Similarly, a hetero alkenylene group comprises one or more carbon-carbon double bond (i.e., comprising two or more carbon atoms and one or more heteroatom, for example as in 3- to 10-membered heteroalkenylene, 3- to 8-membered heteroalkenylene, 5- to 25-membered heteroalkenylene, 6- to 15-membered hetero alkenylene, and 5- to 10- membered heteroalkenylene. In some embodiments, L2is -L3-D-L4-, wherein L3is selected from Ci-io alkylene, C2-10 alkenylene, C2-10 alkynylene, 2- to 10-membered heteroalkylene, and 3- to 10-membered heteroalkenylene, each of which is optionally substituted with one or more Rl lb; D is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more Rl ld; and L4is absent. In some embodiments, L2is -L3-D-L4-, wherein L3is selected from Ci-8 alkylene, C2-8 alkenylene, 2- to 8-membered heteroalkylene, and 3- to 8-membered heteroalkenylene, each of which is optionally substituted with one or more Rllb; D is absent or selected from C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more Rlld; and L4is selected from Cns alkylene, C2-8 alkenylene, 2- to 8-membered heteroalkylene, and 3- to 8- membered heteroalkenylene, each of which is optionally substituted with one or more Rllb. In some embodiments, L2is -L3-D-L4-, wherein L3is selected from Ci-8 alkylene, C2-8 alkenylene, 2- to 8-membered heteroalkylene, and 3- to 8-membered heteroalkenylene, each of which is optionally substituted with one or more Rllb; D is selected from C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more Rlld; and L4is selected from Ci-8 alkylene, C2-8 alkenylene, 2- to 8-membered hetero alkylene, and 3- to 8-membered heteroalkenylene, each of which is optionally substituted with one or more Rl lb. In some embodiments, Rl lbis independently selected at each occurrence from halogen, oxo, Ci-6 alkyl, Ci-e haloalkyl, (Ci-e alkyl)-OH, and -OH. In some embodiments, Rl lbis independently selected at each occurrence from -F, -CH3, -CH2F, -CHF2, -CF3, - CH2CH2F, -CH2CHF2, -CH2OH, and -OH. In some embodiments, Rl lbis independently selected at each occurrence from -CH3, -CH2OH, -CH2F, -CHF2, and -CF3, or two Rl lbjoin to form =0 or C3.6 cycloalkyl, such as cyclopropyl. In some embodiments, D is selected from phenyl and 5- to 8-membered heteroaryl, such as triazole and imidazole. In some embodiments, D is unsubstituted. In some embodiments, D is substituted with one or more Rlld, such as one, two, or three Rlld.

[0169]

[0166] In some embodiments, for a compound of Formula (I), L2is covalently bound to one of W3, W4, W5, W6, or W7; or L2is -L3-D-L4-, wherein L4is covalently bound to one of W3, W4, W5, W6, or W7. For example, L2may be covalently bound to W3— wherein R3bor R3is a bond to L2— as depicted in Formula (I-A). In some embodiments, L2is covalently bound to W4— wherein R4bor R4is a bond to L2— as depicted in Formula (I-B). In some embodiments, L2is covalently bound to W5— wherein R5bor R5is a bond to L2— as depicted in Formula (I-C). In some embodiments, L2is covalently bound to W6— wherein R6bor R6is a bond to L2— as depicted in Formula (I-D). In some embodiments, L2is covalently bound to W7— wherein R7bor R7is a bond to L2— as depicted in Formula (I- E).

[0170]

[0167] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (1-1), (I-Bl), (I-B2), (I-C), (I-Cl), (I- C2), (I-C3), (I-D), (I-Dl), (I-D2), (I-E), or (I-El):

[0171] R20is independently selected at each occurrence from halogen, oxo, =NH, -CN, Ci-6 alkyl, C2-6 alkenyl, C2- e alkynyl, C3-10 carbocycle, -CH2-(C3-IO carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, - S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, -CH2-(C3-io carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-e alkoxy, Ci-6 haloalkoxy, -OR21, -SR21, and -N(R22)(R23);

[0172] R21is independently selected at each occurrence from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and Ci-6 alkyl;

[0173] R22is independently selected at each occurrence from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and Ci-6 alkyl;

[0174] R23is independently selected at each occurrence from H and Ci-e alkyl;

[0175] R24is independently selected at each occurrence from H and Ci-e alkyl; and

[0176] R25is independently selected at each occurrence from alkyl, alkenyl, alkynyl, carbocycle, and 3- to 10-membered heterocycle, wherein Ci-6 alkyl, carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, Ci-e alkyl, Ci-e haloalkyl, Ci-6 alkoxy, C3-10 carbocycle, and 3- to 10-membered heterocycle.

[0177]

[0168] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (1-1), (I-Bl), (I-B2), (I-C), (I-Cl), (I- C2), (I-C3), (I-D), (I-Dl), (I-D2), (I-E), or (I-El), R20is independently selected at each occurrence from halogen, oxo, =NR22, -CN, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.10 carbocycle, -CH2-(C3-IO carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, - N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)(NR22)R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein Ci-6 alkyl, C2.e alkenyl, C2.e alkynyl, C3-10 carbocycle, -CH2-(C3-IO carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NR22, -CN, Ci-e alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, - OR21, -SR21, and -N(R22)(R23).

[0178]

[0169] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (1-1), (I-Bl), (I-B2), (I-C), (I-Cl), (I- C2), (I-C3), (I-D), (I-Dl), (I-D2), (I-E), or (I-El), R20is independently selected at each occurrence from halogen, oxo, =NH, -CN, -NO2, Ci-e alkyl, C2.e alkenyl, C2.e alkynyl, C3-10 carbocycle, -CH2-(C3-IO carbocycle), 3- to 10- membered heterocycle, -CH2-(3- to 10-membered heterocycle), -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3, and - NHCH2CH3, wherein Ci-6 alkyl, C2.e alkenyl, C2.e alkynyl, C3-10 carbocycle, -CH2-(C3-IO carbocycle), 3- to 10- membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, -NO2, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OH, - OCH3, -OCH2CH3, -NH2, -NHCH3, and -NHCH2CH3.

[0179]

[0170] In some embodiments, for a compound of Formula (I-Bl), R5bis -CI E: R7is selected from Ci-6 alkyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -N(R12)(R13), -C(O)R15, -C(O)N(R12)(R13), -S(O)2R15, and - SO2N(R12)(R13), wherein Ci.6alkyl, C3.10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; and R8is hydrogen. In some embodiments, for a compound of Formula (I-B2), R5is hydrogen; R6is selected from hydrogen and -OCH3; R7is selected from Ci-6 alkyl, C3-10 carbocycle, 3- to 10- membered heterocycle, -N(R12)(R13), -C(O)R15, -C(O)N(R12)(R13), -S(O)2R15, and -SO2N(R12)(R13), wherein Ci.6alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; and R8is hydrogen.

[0180]

[0171] In some embodiments, for a compound of Formula (I-Cl), R3is hydrogen or -CH3; R7is selected from Ci-6 alkyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -N(R12)(R13), -C(O)R15, -C(O)N(R12)(R13), -S(O)2R15, and - SO2N(R12)(R13), wherein Ci.6alkyl, C3.10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; and R8is hydrogen. In some embodiments, for a compound of Formula (I-C2), R3bis - CH3; R7is selected from Ci-6 alkyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -N(R12)(R13), -C(O)R15, - C(O)N(R12)(R13), -S(O)2R15, and -SO2N(R12)(R13), wherein Ci-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; and R8is hydrogen. In some embodiments, for a compound of Formula (I-C3), R3is hydrogen or -CH3; R6is selected from hydrogen and -OCH3; R7is selected from C1.6 alkyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -N(R12)(R13), -C(O)R15, -C(O)N(R12)(R13), -S(O)2R15, and -SO2N(R12)(R13), wherein Ci-6 alkyl, C3.10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; and R8is hydrogen.

[0181]

[0172] In some embodiments, for a compound of Formula (I), (I-A), (I-B), (I-Bl), (I-B2), (I-C), (I-Cl), (I-C2), (I-

[0182] C3), (I-D), (I-Dl), (I-D2), (I-E), or (I-El): R1is -CH3; is selected from phenyl and 5- to 7-membered heteroaryl, each of which is optionally substituted with one or more R11; L1is selected from a bond and C1.3 haloalkylene; is selected from absent, phenyl, and 4- to 8-membered heterocycle, wherein the phenyl and 4- to 8-membered heterocycle are optionally substituted with one or more Rlla; and L2is selected from C5-10 alkylene, C5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10-membered heteroalkenylene, each of which is optionally substituted with one or more Rl lb. In some embodiments, R11, when present, is fluorine; Rl la, when present, is -CH3; and Rllb, when present, is selected from halogen, oxo, Ci-e alkyl, Ci-e haloalkyl, (C1-6 alkyl)-OH, and -OH. , alkylene, Ce-s alkenylene, and 6- to 8-membered heteroalkylene, each of which is optionally substituted with one or substituted with one or more Rl la; and L2is selected from Ce-s alkylene and Ce-s alkenylene, each of which is optionally substituted with one or more Rl lb. In some embodiments, R1is -CI E: L’ is C1-2 haloalkylene; ; and L2is Ce-s alkenylene, optionally substituted with one or more Rllb. In some embodiments, R1is -CH3; is selected from L1is C1-2 haloalkylene; is , optionally substituted with one or more Rl la; and L2is -(C1-2 alkylene)-C(O)N(CH3)-(C3-4 alkylene)- or -

[0183] (C1-2 alkylene)-C(O)NH-(C3-4 alkylene)-, wherein C1-2 alkylene and C3.4 alkylene are each independently optionally substituted with one or more Rl lb. In some embodiments, Rl la, when present, is -CH3; and Rllb, when present, is selected from halogen, -CN, oxo, C1-3 alkyl, C1-3 haloalkyl, (C1-3 alkyl)-OH, and -OH. heteroalkylene, each of which is optionally substituted with one or more Rllb. In some embodiments, R1is -CH3; s selected from Ce-s alkylene and Ce-s alkenylene, each of which is optionally substituted with one or more Rl lb. In some embodiments, and L2is -(C1.2 alkylene)-C(O)N(CH3)-(C3-4 alkylene)- or -(C1.2 alkylene)-C(O)NH-(C3-4 alkylene)-, wherein C1.2 alkylene and C3.4 alkylene are each independently optionally substituted with one or more Rllb. In some embodiments, Rl lb, when present, is selected from halogen, -CN, oxo, C1.3 alkyl, C1.3 haloalkyl, (C1.3 alkyl)-

[0184] OH, and -OH.

[0185]

[0175] In some embodiments, a compound of Formula (I) is a compound of the formula: , wherein R50is hydrogen or R11and R51is hydrogen or halogen.

[0186]

[0176] In some embodiments, a compound of Formula (I) is a compound of the formula:

[0187] wherein R50is hydrogen or fluoro.

[0188] In some embodiments, a compound of Formula (I-A) is a compound of the formula:

[0189] In some embodiments, a compound of Formula (I-B) is a compound of the formula:

[0190] wherein R50is hydrogen or fluoro.

[0191] In some embodiments, a compound of Formula (I-C) is a compound of the formula: , wherein R50is hydrogen or fluoro. In some embodiments, a compound of Formula (I-D) is a compound of the formula:

[0192] E) is a compound of the formula: , wherein R50is hydrogen or fluoro. In some embodiments, L1is C1.3 haloalkylene, such as Ci-2 haloalkylene or C1.2 fluoroalkylene. In some embodiments, L2is selected from Ce-s alkylene, Ce-s alkenylene, and 6- to 8-membered heteroalkylene, each of which is optionally substituted with one or more Rllb. In some embodiments, L2is selected from Ce-s alkylene and Ce-s alkenylene, each of which is optionally substituted with one or more Rllb. In some embodiments, L2is -(C1-2 alkylene)-C(O)N(CH3)-(C3-4 alkylene)- or -(C1-2 alkylene)-

[0193] C(O)NH-(C3-4 alkylene)-, wherein C1.2 alkylene and C3.4 alkylene are each independently optionally substituted with one or more Rl lb. In some embodiments, Rl lb, when present, is selected from halogen, -CN, C1.3 alkyl, C1.3 haloalkyl, (C1.3 alkyl)-OH, and -OH. In some embodiments, R50is hydrogen. In some embodiments, R50is fluoro.

[0177] In certain aspects, the present disclosure provides a compound of Formula (I-Cl): or a pharmaceutically acceptable salt or solvate thereof, wherein: is selected from azetidine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more -CI I;,:

[0194] L1is C1.3 haloalkylene;

[0195] L2is selected from C5-10 alkylene, C5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10- membered heteroalkenylene, each of which is optionally substituted with one or more Rllb;

[0196] R1is -CH3;

[0197] R3is hydrogen or -CH3;

[0198] R8is hydrogen;

[0199] R11is selected from fluorine and -CH3; and

[0200] Rllbis selected from halogen, oxo, Ci-6 alkyl, Ci-6 haloalkyl, (Ci-6 alkyl)-OH, and -OH.

[0201]

[0178] In certain aspects, the present disclosure provides a compound of Formula (I-Cl): or a pharmaceutically acceptable salt or solvate thereof, wherein: is selected from azetidine, pyrrolidine, and piperidine;

[0202] L1is selected from -CF2-, -CF2CH2-, and -CF2CH2CH2-;

[0203] L2is selected from C5-10 alkylene, C5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10- membered heteroalkenylene;

[0204] R1is -CH3;

[0205] R8is hydrogen.

[0206]

[0179] In certain aspects, the present disclosure provides a compound of Formula (I-Cl):

[0207] or a pharmaceutically acceptable salt or solvate thereof, wherein: is selected from azetidine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more -CI h:

[0208] L1is Ci-3 haloalkylene;

[0209] L2is C5.io alkenylene optionally substituted with one or more Rl lb;

[0210] R1is -CH3;

[0211] R3is -CH3;

[0212] R7is selected from

[0213] R8is hydrogen;

[0214] R11is selected from fluorine and -CH3; and

[0215] Rllbis selected from halogen, oxo, Ci-6 alkyl, Ci-6 haloalkyl, (Ci-6 alkyl)-OH, and -OH.

[0216]

[0180] In certain aspects, the present disclosure provides a compound of Formula (I-Cl): or a pharmaceutically acceptable salt or solvate thereof, wherein: is selected from azetidine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more -CI h:

[0217] L1is C1.3 haloalkylene;

[0218] L2is selected from 5- to 10-membered hetero alkylene optionally substituted with one or more Rl lb;

[0219] R1is -CH3;

[0220] R3is hydrogen or -

[0221] R7is selected from

[0222] R8is hydrogen;

[0223] R11is selected from fluorine and -CH3; and

[0224] Rllbis selected from halogen, oxo, Ci-6 alkyl, Ci-6 haloalkyl, (Ci-6 alkyl)-OH, and -OH.

[0225]

[0181] In certain aspects, the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein: is selected from phenyl and 5- to 7-membered heteroaryl, each of which is optionally substituted with one or more R11; is absent or selected from phenyl and 4- to 8-membered heterocycle, each of which is optionally substituted with one or more Rl la;

[0226] L1is selected from a bond and C1.3 haloalkylene;

[0227] L2is selected from C5-10 alkylene, C5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10- membered heteroalkenylene, each of which is optionally substituted with one or more Rllb, wherein L2is covalently bound to one of W3, W4, W5, W6, or W7; or L2is -L3-D-L4-, wherein L4is covalently bound to one of W3, W4, W5, W6, or W7;

[0228] L3is selected from Ci-8 alkylene, C2-8 alkenylene, 2- to 8-membered heteroalkylene, and 3- to 8-membered heteroalkenylene, each of which is optionally substituted with one or more Rl lb;

[0229] D is selected from C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more Rl ld;

[0230] L4is selected from Ci-s alkylene, C2-8 alkenylene, 2- to 8-membered heteroalkylene, and 3- to 8-membered heteroalkenylene, each of which is optionally substituted with one or more Rl lb

[0231] W2is N; W3is selected from N(R3b), N, C(R3), and C(O);

[0232] W4is selected from N(R4b), N, C(R4), and C(O);

[0233] W5is selected from N(R5b), N, and C(R5);

[0234] W6is selected from C(R6) and C(O);

[0235] W7is C(R7);

[0236] W8is C(R8);

[0237] W9and W10are each C;

[0238] R1is -CH3;

[0239] R2, R2a, R3a, R4a, R5a, R6a, R7a, R8, and R8aare each independently selected from hydrogen and -CI I;,:

[0240] R3, R4, R5, and R6are each independently selected from a bond to L2, hydrogen, halogen, -CN, C1.3 alkyl, C1.3 haloalkyl, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2;

[0241] R7is selected from a bond to L2, Ci-e alkyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, - N(R12)(R13), -C(O)R15, -C(O)N(R12)(R13), -S(O)2R15, and -SO2N(R12)(R13), wherein Ci.6alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20;

[0242] R3b, R4b, and R5bare each independently selected from a bond to L2, hydrogen, and C1.3 alkyl;

[0243] R11, Rlla, and Rlldare each independently selected at each occurrence from halogen, -CN, Ci-6 alkyl, C2.e alkenyl, C2.e alkynyl, carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), -CH2N(R12)S(O)2(R13), and - P(O)(R17)(R17a), wherein alkyl, alkenyl, alkynyl, carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20;

[0244] Rllbis independently selected at each occurrence from halogen, oxo, -CN, Ci-6 alkyl, C2.e alkenyl, C2.e alkynyl, carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), -CH2N(R12)S(O)2(R13), and - P(O)(R17)(R17a), wherein alkyl, alkenyl, alkynyl, carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20;

[0245] R12is independently selected at each occurrence from hydrogen, Ci-6 alkyl, Ci-e haloalkyl, C2.e alkenyl, C2.e alkynyl, carbocycle, and 3- to 10-membered heterocycle, wherein Ci-6 alkyl, C2.e alkenyl, C2.e alkynyl, carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20;

[0246] R13is independently selected at each occurrence from hydrogen, Ci-6 alkyl, and Ci-6 haloalkyl; or R12and R13, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycle optionally substituted with one, two, or three R20;

[0247] R14is independently selected at each occurrence from hydrogen, Ci-6 alkyl, and Ci-6 haloalkyl;

[0248] R15is independently selected at each occurrence from Ci-6 alkyl, C2.e alkenyl, C2.e alkynyl, carbocycle, and 3- to 10-membered heterocycle, wherein Ci-6 alkyl, C2.e alkenyl, C2.e alkynyl, carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20;

[0249] R17and R17aare each independently selected at each occurrence from Ci-6 alkyl and C3.6 cycloalkyl, wherein Ci-6 alkyl and C3.6 cycloalkyl are optionally substituted with one, two or three R20; or R17and R17a, together with the phosphorous atom to which they are attached, form a 3- to 10-membered heterocycle; R20is independently selected at each occurrence from halogen, oxo, =NH, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, - S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, C1-6alkyl, C1-6haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, - N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; R21is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6 alkyl; R22is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6 alkyl; R23is independently selected at each occurrence from H and C1-6alkyl; R24is independently selected at each occurrence from H and C1-6 alkyl; R25is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C 0carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-10 carbocycle, and 3- to 10-membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0182] In certain aspects, the present disclosure provides a compound of Formula (III): or a pharmaceutically acceptable salt or solvate thereof, wherein: B is selected from 3- to 8-membered heterocycle, optionally substituted with one or more R11a; L1is selected from a bond, C1-6 alkylene, and C1-6 haloalkylene; L2is selected from C5-25 alkylene, C5-25 alkenylene, C5-25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is optionally substituted with one or more R11b, wherein L2is covalently bound to one of W3, W4, W5, W6, or W7; or L2is -L3-D-L4-, wherein L4is covalently bound to one of W3, W4, W5, W6, or W7; L3is selected from C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, 2- to 10-membered heteroalkylene, and 3- to 10-membered heteroalkenylene, each of which is optionally substituted with one or more R11b; D is absent or selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more R11d; L4is selected from C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, 2- to 10-membered heteroalkylene, and 3- to 10-membered heteroalkenylene, each of which is optionally substituted with one or more R11b; W3is selected from N(R3b) and N and W4is selected from C(R4) and C(O); or W3is selected from C(R3) and C(O), and W4is selected from N(R4b) and N; W5is selected from N(R5b), N, and C(R5); W6is selected from N, C(R6), and C(O); W7is selected from N, C(R7), and C(O); R50is hydrogen or halogen; R3, R4, R5, R6, and R7are each independently selected from a bond to L2, hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), - C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20; R3b, R4b, and R5bare each independently selected from a bond to L2, hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -C(O)OR12, - OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, - S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20; R11aand R11dare each independently selected at each occurrence from halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), -CH2N(R12)S(O)2(R13), and - P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R11bis independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), -CH2N(R12)S(O)2(R13), and - P(O)(R17)(R17a), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or R12and R13, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycle optionally substituted with one, two, or three R20; R14is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; R15is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R17and R17aare each independently selected at each occurrence from C1-6 alkyl and C3-6 cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one, two or three R20; or R17and R17a, together with the phosphorous atom to which they are attached, form a 3- to 10-membered heterocycle; R20is independently selected at each occurrence from halogen, oxo, =NH, -CN, C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C3-10 carbocycle, -CH2-(C3-10 carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, - S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10 carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, - N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; R21is independently selected at each occurrence from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; R22is independently selected at each occurrence from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; R23is independently selected at each occurrence from H and C1-6 alkyl; R24is independently selected at each occurrence from H and C1-6alkyl; R25is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, C1-6 alkyl, C1-6haloalkyl, C1-6alkoxy, C3-10carbocycle, and 3- to 10-membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0183] In certain aspects, the present disclosure provides a compound of Formula (III):

[0250] or a pharmaceutically acceptable salt or solvate thereof, wherein: is selected from 3- to 8-membered heterocycle, optionally substituted with one or more R11a; L1is selected from a bond, C1-6alkylene, and C1-6haloalkylene; L2is selected from C5-25alkylene, C5-25alkenylene, C5-25alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is optionally substituted with one or more R11b, wherein L2is covalently bound to one of W3, W4, W5, W6, or W7; W3is selected from N(R3b) and N and W4is selected from C(R4) and C(O); or W3is selected from C(R3) and C(O), and W4is selected from N(R4b) and N; W5is selected from N(R5b), N, and C(R5); W6is selected from N, C(R6), and C(O); W7is selected from N, C(R7), and C(O); R50is hydrogen or halogen; R3, R4, R5, R6, and R7are each independently selected from a bond to L2, hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), - C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20; R3b, R4b, and R5bare each independently selected from a bond to L2, hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -C(O)OR12, - OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, - S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20; R11ais independently selected at each occurrence from halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), - CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), -CH2N(R12)S(O)2(R13), and - P(O)(R17)(R17a), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R11bis independently selected at each occurrence from halogen, oxo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), -CH2N(R12)S(O)2(R13), and - P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or R12and R13, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycle optionally substituted with one, two, or three R20; R14is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl; R15is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R17and R17aare each independently selected at each occurrence from C1-6alkyl and C3-6cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one, two or three R20; or R17and R17a, together with the phosphorous atom to which they are attached, form a 3- to 10-membered heterocycle; R20is independently selected at each occurrence from halogen, oxo, =NH, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, - S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, - N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; R21is independently selected at each occurrence from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; R22is independently selected at each occurrence from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; R23is independently selected at each occurrence from H and C1-6 alkyl; R24is independently selected at each occurrence from H and C1-6 alkyl; R25is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-10 carbocycle, and 3- to 10-membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0184] In some embodiments, a compound of Formula (III) is a compound of the formula: .

[0185] In some embodiments, a compound of Formula (III) is a compound of the formula:

[0251] .

[0186] In some embodiments, for a compound of Formula (III), is selected from azetidine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more R11a. In some embodiments, , each of which is optionally substituted with one or more R11a. In some embodiments, optionally substituted with one or more R11a. In some embodiments, L1is C1-3haloalkylene. In some embodiments, L2is selected from C5-10alkylene, C5-10alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10-membered heteroalkenylene, each of which is optionally substituted with one or more R11b, wherein L2is covalently bound to one of W3, W4, W5, W6, or W7; or L2is -L3-D-L4-, wherein L4is covalently bound to one of W3, W4, W5, W6, or W7; L3is selected from C1-8alkylene, C2-8alkenylene, 2- to 8-membered heteroalkylene, and 3- to 8-membered heteroalkenylene, each of which is optionally substituted with one or more R11b; D is selected from C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more R11d; and L4is selected from C1-8 alkylene, C2-8 alkenylene, 2- to 8-membered heteroalkylene, and 3- to 8-membered heteroalkenylene, each of which is optionally substituted with one or more R11b.

[0187] In certain aspects, the present disclosure provides a compound of the formula: , or a pharmaceutically acceptable salt or solvate thereof, wherein: L2is selected from C5-10alkylene, C5-10alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10- membered heteroalkenylene, each of which is optionally substituted with one or more R11b, wherein L2is covalently bound to one of W3, W4, W5, W6, or W7; or L2is -L3-D-L4-, wherein L4is covalently bound to one of W3, W4, W5, W6, or W7; L3is selected from C1-8alkylene, C2-8alkenylene, 2- to 8-membered heteroalkylene, and 3- to 8-membered heteroalkenylene, each of which is optionally substituted with one or more R11b; D is selected from C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more R11d; L4is selected from C1-8alkylene, C2-8alkenylene, 2- to 8-membered heteroalkylene, and 3- to 8-membered heteroalkenylene, each of which is optionally substituted with one or more R11b; W2is selected from N(R2b), N, C(R2), C(R2)(R2a), and C(O); W3is selected from N(R3b), N, C(R3), C(R3)(R3a), and C(O); W4is selected from N(R4b), N, C(R4), C(R4)(R4a), and C(O); W5is selected from N(R5b), N, C(R5), C(R5)(R5a), and C(O); W6is selected from N(R6b), N, C(R6), C(R6)(R6a), and C(O); W7is selected from N(R7b), N, C(R7), C(R7)(R7a), and C(O); W8is selected from N(R8b), N, C(R8), C(R8)(R8a), and C(O); W9is selected from N, C(R9), and C; W10is selected from N, C(R10), and C; R2, R2a, R3a, R4a, R5a, R6a, R7a, R8, and R8aare each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), - C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20; R3, R4, R5, R6, and R7are each independently selected from a bond to L2, hydrogen, halogen, -CN, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), - C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20; R2band R8bare each independently selected from hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -C(O)OR12, -OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), - CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein each C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C3-10 carbocycle and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20; R3b, R4b, R5b, R6b, and R7bare each independently selected from a bond to L2, hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -C(O)OR12, - OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, - S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20; R9and R10are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, -CH2-(C3-10 carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle), wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, -CH2-(C3-10 carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) is independently optionally substituted with one, two, or three R20; R11dis independently selected at each occurrence from halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), - CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), -CH2N(R12)S(O)2(R13), and - P(O)(R17)(R17a), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R11bis independently selected at each occurrence from halogen, oxo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), -CH2N(R12)S(O)2(R13), and - P(O)(R17)(R17a), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or R12and R13, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycle optionally substituted with one, two, or three R20; R14is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; R15is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R17and R17aare each independently selected at each occurrence from C1-6 alkyl and C3-6 cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one, two or three R20; or R17and R17a, together with the phosphorous atom to which they are attached, form a 3- to 10-membered heterocycle; R20is independently selected at each occurrence from halogen, oxo, =NH, -CN, C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C3-10 carbocycle, -CH2-(C3-10 carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, - S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10 carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, - N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; R21is independently selected at each occurrence from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; R22is independently selected at each occurrence from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; R23is independently selected at each occurrence from H and C1-6 alkyl; R24is independently selected at each occurrence from H and C1-6 alkyl; R25is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-10 carbocycle, and 3- to 10-membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0188] In certain aspects, the present disclosure provides a compound of Formula (II-B) or (II-C): or a pharmaceutically acceptable salt or solvate thereof, wherein: is absent or 4- to 8-membered heterocycle optionally substituted with one or more R11a; L1is C1-3haloalkylene; L2is selected from C5-10 alkylene, C5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10- membered heteroalkenylene, each of which is optionally substituted with one or more R11b; or L2is -L3-D-L4-; L3is selected from C1-8alkylene, C2-8alkenylene, 2- to 8-membered heteroalkylene, and 3- to 8-membered heteroalkenylene, each of which is optionally substituted with one or more R11b; D is selected from C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more R11d; L4is selected from C1-8alkylene, C2-8alkenylene, 2- to 8-membered heteroalkylene, and 3- to 8-membered heteroalkenylene, each of which is optionally substituted with one or more R11b; R3and R8are each independently selected from hydrogen and -CH3; R7is selected from C3-8 carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20; R5bis selected from hydrogen and C1-3 alkyl; R50is selected from hydrogen and halogen; R11aand R11dare each independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), -CH2N(R12)S(O)2(R13), and - P(O)(R17)(R17a), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R11bis independently selected at each occurrence from halogen, oxo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), -CH2N(R12)S(O)2(R13), and - P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or R12and R13, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycle optionally substituted with one, two, or three R20; R14is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl; R15is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R17and R17aare each independently selected at each occurrence from C1-6alkyl and C3-6cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one, two or three R20; or R17and R17a, together with the phosphorous atom to which they are attached, form a 3- to 10-membered heterocycle; R20is independently selected at each occurrence from halogen, oxo, =NH, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, - S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, - N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; R21is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6 alkyl; R22is independently selected at each occurrence from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6 alkyl; R23is independently selected at each occurrence from hydrogen and C1-6alkyl; R24is independently selected at each occurrence from hydrogen and C1-6 alkyl; and R25is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-10 carbocycle, and 3- to 10-membered heterocycle.

[0189] In some embodiments, the present disclosure provides a compound of Formula (II-B) or (II-C): or a pharmaceutically acceptable salt or solvate thereof, wherein: is absent or 4- to 8-membered heterocycle optionally substituted with one or more R11a; L1is C1-3 haloalkylene; L2is selected from C5-10alkylene, C5-10alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10- membered heteroalkenylene, each of which is optionally substituted with one or more R11b; R3, R5b, and R8are each independently selected from hydrogen and -CH3; R7is selected from C3-8 carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20; R50is selected from hydrogen and halogen; R11ais independently selected at each occurrence from halogen, C1-3 alkyl, and C1-3 haloalkyl; R11bis independently selected at each occurrence from halogen, oxo, -CN, C1-3 alkyl, and -OH; and R20is independently selected at each occurrence from halogen, oxo, -CN, and C1-6alkyl.

[0190] In some embodiments, the present disclosure provides a compound of Formula (II-C):

[0252] or a pharmaceutically acceptable salt or solvate thereof, wherein: is absent or 4- to 8-membered heterocycle optionally substituted with one or more R11a; L1is C1-3haloalkylene; L2is selected from C5-10 alkylene, C5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10- membered heteroalkenylene, each of which is optionally substituted with one or more R11b; R3is hydrogen; R8is selected from hydrogen and -CH3; R7is selected from R50is selected from hydrogen and halogen; R11ais independently selected at each occurrence from halogen, C1-3alkyl, and C1-3haloalkyl; R11bis independently selected at each occurrence from halogen, oxo, -CN, C1-3 alkyl, and -OH; and R20is independently selected at each occurrence from halogen, oxo, -CN, and C1-6 alkyl.

[0191] In some embodiments, the present disclosure provides a compound of Formula (II-C): or a pharmaceutically acceptable salt or solvate thereof, wherein: is 4- to 8-membered heterocycle optionally substituted with one or more R11a; L1is C1-3haloalkylene; L2is selected from C5-10 alkylene, C5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10- membered heteroalkenylene, each of which is optionally substituted with one or more R11b; R3is selected from hydrogen and -CH3; R50is selected from hydrogen and halogen; R11ais independently selected at each occurrence from halogen, C1-3alkyl, and C1-3haloalkyl; and R11bis independently selected at each occurrence from halogen, oxo, -CN, C1-3alkyl, and -OH.

[0192] In some embodiments, the present disclosure provides a compound of Formula (II-C): or a pharmaceutically acceptable salt or solvate thereof, wherein: is 4- to 6-membered heterocycle; L1is C1-3 haloalkylene; L2is selected from C5-10alkylene, C5-10alkenylene, and 5- to 10-membered heteroalkylene; R3is selected from hydrogen and -CH3; R8is hydrogen; R50is selected from hydrogen and halogen.

[0193] In some embodiments, the present disclosure provides a compound of Formula (II-C):

[0253] or a pharmaceutically acceptable salt or solvate thereof, wherein: L1is -CF2CH2-; L2is 5- to 10-membered heteroalkylene, wherein the heteroalkylene comprises one oxygen atom; R3is selected from hydrogen and -CH3; R8is hydrogen; R50is selected from hydrogen and halogen.

[0194] In some embodiments, the present disclosure provides a compound of Formula (II-C): or a pharmaceutically acceptable salt or solvate thereof, wherein: L1is -CF2-; L2is selected from C5-10alkenylene; R3is selected from hydrogen and -CH3; R8is hydrogen; R50is selected from hydrogen and halogen.

[0195] In some embodiments, a compound of Formula (II-B) is a compound of the formula: hydrogen and fluoro. In some embodiments, R5bis -CH3; R8is hydrogen; and R50is hydrogen. In some embodiments, R5bis -CH3; R8is hydrogen; and R50is fluoro. In some embodiments, R7is selected from , . In some embodiments, R5bis -CH3; R8is hydrogen; R50is hydrogen; and R7is selected from . In some embodiments, R5bis -CH3; R8is hydrogen; R50is fluoro; and R7is selected from . In some embodiments, R5bis -CH3; R8is hydrogen; R50is selected from hydrogen and fluoro; and R7is . In some embodiments, R5bis -CH3; R8is hydrogen; R50is selected from hydrogen and fluoro; and R7is . In some embodiments, R5bis -CH3; R8is hydrogen; R50is selected from hydrogen and fluoro; and R7is .

[0196] In some embodiments, a compound of Formula (II-C) is a compound of the formula:

[0254] hydrogen; and R50is selected from hydrogen and fluoro. In some embodiments, R3is selected from hydrogen and - CH3; R8is hydrogen; and R50is hydrogen. In some embodiments, R3is selected from hydrogen and -CH3; R8is hydrogen; and R50is fluoro. In some embodiments, R3is hydrogen; R8is hydrogen; and R50is hydrogen. In some embodiments, R3is hydrogen; R8is hydrogen; and R50is fluoro. In some embodiments, R3is -CH3; R8is hydrogen; and R50is hydrogen. In some embodiments, R3is -CH3; R8is hydrogen; and R50is fluoro. In some embodiments, R7is selected from . In some embodiments, R3is selected from hydrogen and - CH3; R8is hydrogen; R50is hydrogen; and R7is selected from , , . In some embodiments, R3is selected from hydrogen and -CH3; R8is hydrogen; R50is fluoro; and R7is selected from , . In some embodiments, R3is hydrogen; R8is hydrogen; R50is selected from hydrogen and fluoro; and R7is selected from . In some embodiments, R3is hydrogen; R8is hydrogen; R50is hydrogen; and R7is selected from . In some embodiments, R3is hydrogen; R8is hydrogen; R50is fluoro; and R7is selected from , , and , d from In some embodiments, R3is selected from hydrogen and -CH3; R8is hydrogen; R50is selected from hydrogen and fluoro; and R7is . In some embodiments, R3is selected from hydrogen and -CH3; R8is hydrogen; R50is selected from hydrogen and fluoro; and R7is . In some embodiments, R3is selected from hydrogen and -CH3; R8is hydrogen; R50is selected from hydrogen and fluoro; and .

[0197] Embodiments disclosed herein that refer to a compound of Formula (I), (I-A), (I-B), (I-B1), (I-B2), (I-C),(I-C1), (I-C2), (I-C3), (I-D), (I-D1), (I-D2), (I-E), and / or (I-E1) are also intended to apply to a compound of Formula (I-1), (II-B), (II-C), and (III) unless the context of the embodiment clearly dictates otherwise (e.g., the embodiment refers solely to a variable not present in the compound of Formula (I-1), (II-B), (II-C), or (III), such as R1).

[0198] In some embodiments, a compound of Formula (I) is a compound of the formula: solvate thereof.

[0199] In certain aspects, the present disclosure provides a compound of Formula (I-1):

[0255] or a pharmaceutically acceptable salt or solvate thereof, wherein: A is selected from C5-7carbocycle and 5- to 7-membered heterocycle, each of which is optionally substituted with one or more R11; is absent or selected from C3-8 carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more R11a; L1is selected from a bond, C1-6alkylene, and C1-6haloalkylene; L2is selected from C5-25 alkylene, C5-25 alkenylene, C5-25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is optionally substituted with one or more R11b, wherein L2is covalently bound to one of W3, W4, W5, W6, or W7; W3is selected from N(R3b), N, C(R3), and C(O); W4is selected from N(R4b), N, C(R4), and C(O); W5is selected from N(R5b), N, and C(R5); W6is selected from C(R6) and C(O); W7is C(R7); R1is C1-3 alkyl optionally substituted with one or more R11c; R8is selected from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10- membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), - N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), - N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), - CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20; R3, R4, R5, R6, and R7are each independently selected from a bond to L2, hydrogen, halogen, -CN, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), - C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20; R3b, R4b, and R5bare each independently selected from a bond to L2, hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -C(O)OR12, - OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, - S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20; R11and R11aare each independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), -CH2N(R12)S(O)2(R13), and - P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R11bis independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), -CH2N(R12)S(O)2(R13), and - P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R11cis independently selected at each occurrence from halogen, -OR12, and -N(R12)(R13); R12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or R12and R13, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycle optionally substituted with one, two, or three R20; R14is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl; R15is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R17and R17aare each independently selected at each occurrence from C1-6alkyl and C3-6cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one, two or three R20; or R17and R17a, together with the phosphorous atom to which they are attached, form a 3- to 10-membered heterocycle; R20is independently selected at each occurrence from halogen, oxo, =NH, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, - S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, - N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; R21is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6 alkyl; R22is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6 alkyl; R23is independently selected at each occurrence from H and C1-6alkyl; R24is independently selected at each occurrence from H and C1-6 alkyl; R25is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-10 carbocycle, and 3- to 10-membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0200] In some embodiments, the compound of Formula (I-1) is a compound of Formula (I-B1) or (I-B2):

[0201] In some embodiments, the compound of Formula (I-1) is a compound of Formula (I-C1), (I-C2), or (I-C3): C3), or a pharmaceutically acceptable salt or solvate thereof.

[0202] In some embodiments, for a compound of Formula (I-1), (I-B1), (I-B2), (I-C1), (I-C2), or (I-C3), R1 is -CH3. In some embodiments, for a compound of Formula (I-1), (I-C1), or (I-C3), R3is selected from hydrogen, -CN, -OR12, and -CH3. In some embodiments, for a compound of Formula (I-1), (I-B2), or (I-C3), R6is selected from hydrogen, -OR12, and C1-6 alkyl optionally substituted with one, two, or three R20, and wherein R12is selected from C1-6 alkyl. In some embodiments, for a compound of Formula (I-1), (I-B1), (I-B2), (I-C1), (I-C2), or (I-C3), R8is hydrogen.

[0203] In some embodiments, for a compound of Formula (I-1), (I-B1), (I-B2), (I-C1), (I-C2), or (I-C3), R7 isselected from C1-6 alkyl, C3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and -N(R12)(R13), wherein C1-6 alkyl, C3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one, two, or three R20. In some embodiments, R7is selected from , .

[0204] In some embodiments, for a compound of Formula (I-1), (I-B1), (I-B2), (I-C1), (I-C2), or (I-C3), is selected from phenyl and 5- to 7-membered heteroaryl, each of which is optionally substituted with one or more R11. In some embodiments, is selected from , , , , . In some embodiments, R11is independently selected from fluorine and -CH3.

[0205] In some embodiments, for a compound of Formula (I-1), (I-B1), (I-B2), (I-C1), (I-C2), or (I-C3), L1 is C1-3haloalkylene. In some embodiments, L1is selected from -CF2-, -CF2CH2-, and -CF2CH2CH2-.

[0206] In some embodiments, for a compound of Formula (I-1), (I-B1), (I-B2), (I-C1), (I-C2), or (I-C3), is selected from absent, phenyl, and 4- to 8-membered heterocycle, wherein the phenyl and 4- to 8-membered heterocycle are optionally substituted with one or more R11a. In some embodiments, is selected from azetidine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more -CH3.

[0207] In some embodiments, for a compound of Formula (I-1), (I-B1), (I-B2), (I-C1), (I-C2), or (I-C3), L2 isselected from C6-15alkylene, C6-15alkenylene, C6-15alkynylene, 6- to 15-membered heteroalkylene, and 6- to 15- membered heteroalkenylene, each of which is optionally substituted with one or more R11b. In some embodiments, L2is selected from C5-10 alkylene, C5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10-membered heteroalkenylene, each of which is optionally substituted with one or more R11b. In some embodiments, the alkenylene and heteroalkenylene contain one carbon-carbon double bond. In some embodiments, the heteroalkylene and heteroalkenylene comprise at least one oxygen or nitrogen atom.

[0208] In some embodiments, for a compound of Formula (I-1), (I-B1), or (I-B2), R5 is hydrogen; R5b is -CH3; R6is selected from hydrogen and -OCH3; R7is selected from C1-6 alkyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -N(R12)(R13), -C(O)R15, -C(O)N(R12)(R13), -S(O)2R15, and -SO2N(R12)(R13), wherein C1-6alkyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; and R8is hydrogen.

[0209] In some embodiments, for a compound of Formula (I-1), (I-C1), (I-C2), or (I-C3), R3 is hydrogen or -CH3;R3bis -CH3; R6is selected from hydrogen and -OCH3; R7is selected from C1-6alkyl, C3-10carbocycle, 3- to 10- membered heterocycle, -N(R12)(R13), -C(O)R15, -C(O)N(R12)(R13), -S(O)2R15, and -SO2N(R12)(R13), wherein C1-6alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; and R8is hydrogen.

[0210] Small molecule SOS1 inhibitors suitable for use in the subject methods—including the synergisticinhibition of proliferation of EGFR-mediated cancer cells in combination with amivantamab—include compounds of Formula (I); Formula (I-A); Formula (I-B); Formula (I-1), encompassing Compound A; Formula (I-B1); Formula (I-B2); Formula (I-C); Formula (I-C1); Formula (I-C2); Formula (I-C3); Formula (I-D); Formula (I-D1); Formula (I- D2); Formula (I-E); Formula (I-E1); Formula (II-B); Formula (II-C); and Formula (III). Exemplary small molecule SOS1 inhibitors include, but are not limited to, compounds selected from Table 1 (including Compound A), or a salt or solvate thereof.

[0211] In some embodiments, a compound disclosed herein, such as a compound of Formula (I), (I-A), (I-B), (I-1),(I-B1), (I-B2), (I-C), (I-C1), (I-C2), (I-C3), (I-D), (I-D1), (I-D2), (I-E), (I-E1), (II-B), (II-C), or (III), is provided as a substantially pure stereoisomer. In some embodiments, the stereoisomer is provided in at least 80% enantiomeric excess, such as at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.9% enantiomeric excess.

[0212] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. Insome embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0213] In some embodiments, the compounds described herein possess acidic or basic groups and therefore reactwith any of a number of inorganic or organic bases or inorganic or organic acids to form a pharmaceutically acceptable salt. In some embodiments, such salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0214] In some embodiments, the compounds described herein exist as solvates. In some embodiments aremethods of treating diseases by administering such solvates. Further described herein are methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0215] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in someembodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or MeOH. In addition, the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

[0216] The chemical entities described herein can be synthesized according to one or more illustrative schemesherein and / or techniques known in the art. Materials used herein are either commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or by any particular substituents, which are employed for illustrative purposes. Although various steps are described and depicted in Schemes 1-8, the steps in some cases may be performed in a different order than the order shown in Schemes 1-8. Various modifications to these synthetic reaction schemes may be made and will be suggested to one skilled in the art having referred to the present disclosure. Numberings or R groups in each scheme typically have the same meanings as those defined elsewhere herein unless otherwise indicated.

[0217] Unless specified to the contrary, the reactions described herein take place at atmospheric pressure,generally within a temperature range from -10 °C to 200 °C. Further, except as otherwise specified, reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -10 °C to about 110 °C over a period of about 1 to about 24 hours; reactions left to run overnight average a period of about 16 hours.

[0218] In general, compounds of the disclosure may be prepared by the following reaction schemes:Scheme 1

[0219] In some embodiments, a compound of Formula 1e may be prepared according to Scheme 1. For example,heteroaryl amine 1b can be formed from chloride 1a via a nucleophilic aromatic substitution reaction. Substitution of the lactam can proceed under basic conditions to give diene 1c, which can undergo a cross metathesis reaction— such as Grubbs cross metathesis reaction—to form macrocycle 1d. Optionally, 1d may be subjected to one or more subsequent reactions, such as a hydrogenation reaction, to provide a compound of Formula 1e. Scheme 2

[0256]

[0220] Similarly, in some embodiments, a compound of Formula 2e may be prepared according to Scheme 2. Forexample, heteroaryl amine 2b can be formed from chloride 2a via a nucleophilic aromatic substitution reaction. Substitution of the lactam can proceed under basic conditions to give diene 2c, which can undergo a cross metathesis reaction—such as Grubbs cross metathesis reaction—to form macrocycle 2d. Optionally, 2d may be subjected to one or more subsequent reactions, such as a hydrogenation reaction, to provide a compound of Formula 2e. Scheme 3

[0221] In some embodiments, a compound of Formula 3e may be prepared according to Scheme 3. For example,heteroaryl amine 3b can be formed from chloride 3a via a substitution reaction. Substitution of the lactam can give protected amine 3c. Hydrolysis of the ester can form carboxylic acid 3d, which can undergo deprotection and peptide coupling reactions to afford macrocycle of Formula 3e. Scheme 4

[0222] Similarly, in some embodiments, a compound of Formula 4e may be prepared according to Scheme 4. Forexample, heteroaryl amine 4b can be formed from chloride 4a via a substitution reaction. Substitution of the lactam can give protected amine 4c. Hydrolysis of the ester can form carboxylic acid 4d, which can undergo deprotection and peptide coupling reactions to afford a macrocycle of Formula 4e. Scheme 5

[0223] In some embodiments, a compound of Formula 5g may be prepared according to Scheme 5. For example,heteroaryl amine 3c can be formed by coupling chloride 5a with amine 5b. Oxidation of the alcohol can give aldehyde 5d, which can be followed with substitution of the phenol to give 5e. Removal of the amine protecting group can afford 5f, which can undergo a reductive amination to form a macrocycle of Formula 5g. Scheme 6

[0224] In some embodiments, a compound of Formula 6f may be prepared according to Scheme 6. For example,heteroaryl amine 6c can be formed by coupling chloride 1a with amine 6b. Substitution of the phenol to olefin 6d can be followed by installation of a second olefin to give diene 6e. A cross metathesis reaction—such as Grubbs cross metathesis reaction—can be followed by hydrogenation of the resulting double bond to provide a macrocycle of Formula 6f. Scheme 7

[0257]

[0258]

[0225] In some embodiments, a compound of Formula 7e may be prepared according to Scheme 7. For example, heteroaryl amine 7b can be formed by coupling chloride 7a with amine 5b. Substitution of the phenol can give 7c. Ester hydrolysis and deprotection of the amine can give 7d, which can be cyclized to form a macrocycle of Formula 7e via a peptide coupling reaction.

[0259] Scheme 8

[0260]

[0226] In some embodiments, a compound of Formula 8g may be prepared according to Scheme 8. For example, substitution of lactam 8a with a suitable bromo dioxolane (8b) can give acetal 8c. Nucleophilic aromatic substitution with amine 8d can provide heteroaryl amine 8e, which can be treated with a suitable acid, such as HC1, to remove the Boc protecting group and reveal the aldehyde. Finally, cyclization of 8f can proceed via reductive amination conditions to give a macrocycle of Formula 8g.

[0261]

[0227] Synthetic procedures for certain compounds may be found in PCT / US2022 / 018584, U.S. Pat. No.

[0262] 11,648,254, PCT / US2023 / 065963, and U.S. App. No. 18 / 328,109, each of which is incorporated by reference in its entirety, including any compounds, formulas, recitations of compound variables, and synthetic methods disclosed therein. In some embodiments, a SOS1 inhibitor of the present disclosure is a compound described in U.S. Pat. No.

[0263] 11,648,254, which is incorporated herein by reference in its entirety. In some embodiments, a SOS1 inhibitor of the present disclosure is a compound described in U.S. Pat. No. 11,912,708, which is incorporated herein by reference in its entirety.

[0264]

[0228] In some embodiments, a compound of the present disclosure, for example, a compound of a formula given in Table 1, was synthesized according to one of the general routes outlined in Schemes 1-8 or by methods generally known in the art. In some embodiments, exemplary compounds may include, but are not limited to, a compound selected from Table 1, or a salt or solvate thereof. Table 1

[0265]

[0266]

[0229] In some embodiments, the compounds of the present disclosure exhibit one or more functional characteristics described herein. For example, a subject compound is capable of reducing Ras signaling output. In some instances, a subject compound is capable of disrupting a Ras-SOS interaction, including disrupting interaction or binding between a mutant Kras (e.g., Kras G12C) and SOS1 , or between a wildtype Kras and SOS1, thereby reducing Ras signaling output. In some embodiments, a subject compound binds specifically to a SOS protein, including SOS1. In some embodiments, the IC50 of a subject compound (including those shown in Table 1) for a SOS protein is less than about 5 pM, less than about 1 pM, less than about 50 nM, less than about 10 nM, less than about 1 nM, less than about 0.5 nM, less than about 100 pM, or less than about 50 pM, as measured in an in vitro assay known in the art or exemplified herein.

[0267]

[0230] A reduction in Ras signaling output can be evidenced by one or more members of the following: (i) an increase in steady state level of GDP -bound Ras protein; (ii) a reduction in steady state level of GTP-bound Ras protein; (iii) a reduction of phosphorylated AKTs473, (iv) a reduction of phosphorylated ERKT202 / y204, (v) a reduction of phosphorylated S6S235 / 236, (vi) reduction (e.g., inhibition) of cell growth of Ras-driven tumor cells (e.g., those derived from a tumor cell line disclosed herein), and (vii) an interference or disruption of the interaction or binding between a SOS protein (e.g., SOS1) with a Ras protein such as a wildtype or a mutant Ras. In some cases, the reduction in Ras signaling output can be evidenced by two, three, four, five, six, or all of (i)-(vii) above.

[0268]

[0231] It shall be understood that different aspects of the invention can be appreciated individually, collectively, or in combination with each other. Various aspects of the invention described herein may be applied to any of the particular applications disclosed herein. The compositions of matter including compounds of any formulae disclosed herein in the compounds section of the present disclosure may be utilized in the methods section including methods of use and production disclosed herein, or vice versa.

[0269] Kits

[0270]

[0232] Another aspect of the present disclosure provides a kit for use in reducing proliferation of cancer cells comprising an EGFR mutation, such as an EGFR exon 20 insertion. Typically, the kit comprises: (1) a composition comprising a SOS1 inhibitor of Formula (I), (I-A), (I-B), (1-1), (I-Bl), (I-B2), (I-C), (I-Cl), (I-C2), (I-C3), (I-D), (I- Dl), (I-D2), (I-E), (I-El), (II-B), (II-C), or (III); (2) a composition comprising amivantamab; and (3) instructions for using the composition(s) of (1) and (2). In some embodiments, the small molecule SOS1 inhibitor is a compound described in Table 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, instructions for contacting the cells in vitro, ex vivo, or in vivo are provided. In some embodiments, the SOS1 inhibitor and amivantamab are formulated in the same unit dosage form. In some embodiments, the SOS1 inhibitor and amivantamab are formulated in different unit dosage forms. In some embodiments, the kit can comprise a multi -day supply, including instructions directing the multi-day administration.

[0271] Pharmaceutical compositions and methods of administration

[0272]

[0233] In certain aspects, the present disclosure provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0273]

[0234] A compound of Formula (I), (I-A), (I-B), (1-1), (I-Bl), (I-B2), (I-C), (I-Cl), (I-C2), (I-C3), (I-D), (I-Dl), (I- D2), (I-E), (I-El), (II-B), (II-C), or (III), or a pharmaceutically acceptable salt or solvate thereof, may be administered to a subject in a biologically compatible form suitable for administration to treat or prevent a disease, disorder or condition. A compound described herein may be administered in any pharmacological form including a therapeutically effective amount of a compound of Formula (I), (I-A), (I-B), (1-1), (I-B 1), (I-B2), (I-C), (I-C 1), (I- C2), (I-C3), (I-D), (I-Dl), (I-D2), (I-E), (I-El), (II-B), (II-C), or (III), or a pharmaceutically acceptable salt or solvate thereof, alone or in combination with a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), (I-A), (I-B), (1-1), (I-Bl), (I-B2), (I-C), (I-Cl), (I-C2), (I-C3), (I-D), (I-Dl), (I-D2), (I-E), (I-El), (II-B), (II-C), or (III), or a pharmaceutically acceptable salt or solvate thereof.

[0274]

[0235] In some embodiments, a compound described herein is administered as a pure chemical. In some embodiments, a compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0275]

[0236] Accordingly, provided herein is a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt, together with one or more pharmaceutically acceptable excipients. The excipient(s) (or carrier(s)) is acceptable or suitable if the excipient is compatible with the other ingredients of the composition and not deleterious to the recipient of the composition.

[0276]

[0237] In practicing any of the subject methods, the compounds described herein may be administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon, for example, the condition and disorder of the recipient. By way of example only, a compound described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant. The administration can also be by direct injection at the site of a diseased tissue or organ. In some embodiments, a compound described herein is administered orally.

[0238] In practicing any of the subject methods, a pharmaceutical composition suitable for oral administration may be presented as a discrete unit such as a capsule, cachet or tablet, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste.

[0277]

[0239] Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free -flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.

[0278]

[0240] In some embodiments, a pharmaceutical composition is formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen- free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0279]

[0241] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0280]

[0242] Pharmaceutical compositions may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0281] EXAMPLES

[0282]

[0243] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.

[0283]

[0244] Example 1: Sequences

[0284]

[0245] Human K-Ras4b (SEQ ID NO. 1 ) :

[0285] 1 MTEYKL VVVG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQ WIDGET

[0286] 51 CLLDILDTAG QEEYSAMRDQ YMRTGEGFLC VFAINNTKSF EDIHHYREQI

[0287] 101 KRVKDSEDVP MVLVGNKCDL PSRTVDTKQA QDLARSYGIP FIETSAKTRQ

[0288] 151 GVDDAFYTLV REIRKHKEKM SKDGKKKKKK SKTKCVIM

[0289]

[0246] Human SOS1 (SEQ ID NO. 2):

[0290] 1 MQAQQLPYEF FSEENAPKWR GLLVPALKKV QGQVHPTLES NDDALQYVEE

[0291] 51 LILQLLNMLC QAQPRSASDV EERVQKSFPH PIDKWAIADA QSAIEKRKRR

[0292] 101 NPLSLPVEKI HPLLKEVLGY KIDHQVSVYI VAVLEYISAD ILKLVGNYVR

[0293] 151 NIRHYEITKQ DIKVAMCADK VLMDMFHQDV EDINILSLTD EEPSTSGEQT

[0294] 201 YYDLVKAFMA EIRQYIRELN LIIKVFREPF VSNSKLFSAN DVENIFSRIV

[0295] 251 DIHELSVKLL GHIEDTVEMT DEGSPHPLVG SCFEDLAEEL AFDPYESYAR

[0296] 301 DILRPGFHDR FLSQLSKPGA ALYLQSIGEG FKEAVQYVLP RLLLAPVYHC

[0297] 351 LHYFELLKQL EEKSEDQEDK ECLKQAITAL LNVQSGMEKI CSKSLAKRRL

[0298] 401 SESACRFYSQ QMKGKQLAIK KMNEIQKNID GWEGKDIGQC CNEFIMEGTL

[0299] 451 TRVGAKHERH IFLFDGLMIC CKSNHGQPRL PGASNAEYRL KEKFFMRKVQ

[0300] 501 INDKDDTNEY KHAFEIILKD ENSVIFSAKS AEEKNNWMAA LISLQYRSTL

[0301] 551 ERMLDVTMLQ EEKEEQMRLP SADVYRFAEP DSEENIIFEE NMQPKAGIPI

[0302] 601 IKAGTVIKLI ERLTYHMYAD PNFVRTFLTT YRSFCKPQEL LSLIIERFEI

[0303] 651 PEPEPTEADR IAIENGDQPL SAELKRFRKE YIQPVQLRVL NVCRHWVEHH

[0304] 701 FYDFERDAYL LQRMEEFIGT VRGKAMKKWV ESITKIIQRK KIARDNGPGH

[0305] 751 NITFQSSPPT VEWHISRPGH IETFDLLTLH PIEIARQLTL LESDLYRAVQ

[0306] 801 PSELVGSVWT KEDKEINSPN LLKMIRHTTN LTLWFEKCIV ETENLEERVA

[0307] 851 WSRIIEILQ VFQELNNFNG VLEWSAMNS SPVYRLDHTF EQIPSRQKKI

[0308] 901 LEEAHELSED HYKKYLAKLR SINPPCVPFF GIYLTNILKT EEGNPEVLKR

[0309] 951 HGKELINFSK RRKVAEITGE IQQYQNQPYC LRVESDIKRF FENLNPMGNS

[0310] 1001 MEKEFTDYLF NKSLEIEPRN PKPLPRFPKK YS YPLKSPGV RPSNPRPGTM

[0311] 1051 RHPTPLQQEP RKISYSRIPE SETESTASAP NSPRTPLTPP PASGASSTTD

[0312] 1101 VCSVFDSDHS SPFHSSNDTV FIQVTLPHGP RSASVSSISL TKGTDEVPVP

[0313] 1151 PPVPPRRRPE SAPAESSPSK IMSKHLDSPP AIPPRQPTSK AYSPRYSISD

[0314] 1201 RTSISDPPES PPLLPPREPV RTPDVFSSSP LHLQPPPLGK KSDHGNAFFP

[0315] 1251 NSPSPFTPPP PQTPSPHGTR RHLPSPPLTQ EVDLHSIAGP PVPPRQSTSQ

[0316] 1301 HIPKLPPKTY KREHTHPSMH RDGPPLLENA HSS

[0317]

[0247] Example 2: SOS purification

[0248] A SOS construct or a variant thereof is His-tagged. E. coli cultures are induced in a fermenter, harvested, and lysed in lysis buffer, for example, in 25 mM Tris HC1 7.5, 500 mM NaCl, 20 mM Imidazol, Complete EDTA- free (Roche)). For immobilized metal ion affinity chromatography (IMAC), the centrifuged lysate (50,000 x g, 45 min, 40) is incubated with 30 mL Ni-NTA (Macherey -Nagel; #745400.100) in a spinner flask (16 h, 40) and subsequently transferred to a chromatography column connected to a chromatography system, e.g., an Akta chromatography system. The column is rinsed with wash buffer, e.g., in 25 mM Tris HC1 7.5, 500 mM NaCl, 20 mM Imidazol and the bound protein is eluted with a linear gradient (0-100%) of elution buffer (25 mM Tris HC1 7.5, 500 mM NaCl, 300 mM Imidazol). The main fractions of the elution peak (monitored by OD280) containing homogenous HislO-hSOS is pooled.

[0318]

[0249] Example 3: Ras-SOS interaction assay

[0319]

[0250] The ability of any compound of the present disclosure to reduce a Ras protein signaling output by, e.g., interfering or disrupting interaction (or binding) between SOS1 and a Ras protein can be assessed in vitro. For example, the equilibrium interaction of human SOS1 (hSOSl) with human wildtype Kras or K-Ras mutant (e.g., hK-Ras G12C mutant, or hK-Ras G12C) can be assessed as a proxy or an indication for a subject compound’s ability to inhibit SOS. Detection of such interaction is achieved by measuring homogenous time-resolved fluorescence resonance energy transfer (HTRF) from (i) a fluorescence resonance energy transfer (FRET) donor (e.g., antiGST-Europium) that is bound to GST-tagged K-Ras G12C to (ii) a FRET acceptor (e.g., anti-6His-XL665) bound to a His-tagged hSOSl .

[0320]

[0251] The assay buffer can contain 5 mM HEPES pH 7.4, 150 mM NaCl, 10 mM EDTA, 1 mM DTT, 0.05% BSA, 0.0025% (v / v) Igepal and 100 mM KF. A Ras working solution is prepared in assay buffer containing typically 10 nM of the protein construct (e.g., GST-tagged hK-Ras G12C) and 2 nM of the FRET donor (e.g., antiGST-Eu(K) from Cisbio, France). A SOS1 working solution is prepared in assay buffer containing typically 10 nM of the protein construct (e.g., His-hSOSl) and 10 nM of the FRET acceptor (e.g., anti-6His-XL665 from Cisbio, France). An inhibitor control solution is prepared in assay buffer containing 10 nM of the FRET acceptor without the SOS1 protein.

[0321]

[0252] A fixed reaction mixture with or without test compound is transferred into a 384-well plate. Ras working solution is added to all wells of the test plate. SOS1 working solution is added to all wells except for those that are subsequently filled with the inhibitor control solution. After approximately 60 min incubation, the fluorescence is measured with a MIOOOPro plate reader (Tecan) using HTRF detection (excitation 337 nm, emission 1 : 620nm, emission 2: 665nm). Compounds are tested in duplicate at different concentrations (for example, 10 pM, 2.5 pM, 0.63 pM, 0.16 pM, 0.04 pM, 0.01 pM test compound). The ratiometric data (i.e., emission 2 divided by emission 1) is used to calculate IC50 values against SOS1 using GraphPad Prism (GraphPad software).

[0322]

[0253] Example 4: Ras-SOS cellular growth inhibition assay

[0323]

[0254] The ability of any compound of the present disclosure to inhibit SOS 1 -mediated signaling and hence Ras protein signaling can be demonstrated by inhibiting growth of a given Kras mutant cell line.

[0324]

[0255] Growth of cells with K-Ras G12C mutation: MIA PaCa-2 (ATCC CRL-1420) and NCI-H1792 (ATCC CRL-5895) cell lines comprise a G12C mutation and can be used to assess Ras cellular signaling in vitro, e.g., in response to a subject compound of the present disclosure. This cellular assay can also be used to discern selective inhibition of subject compounds against certain types of Kras mutants, e.g., more potent inhibition against Kras G12D relative to Kras G12C mutant, by using MIA PaCa-2 (G12C driven tumor cell line) as a comparison. Cell culture medium (comprising, for example, MIA PaCa-2 cells) is prepared with DMEM / Ham's F12 (e.g., with stable Glutamine, 10% FCS, and 2.5% Horse Serum). NCI-H1792 culture medium is prepared with RPMI 1640 (e.g., with stable Glutamine) and 10% FCS. A CellTiter-Glo (CTG) luminescent based assay (Promega) is used to assess growth of the cells, as a measurement of the ability of the compounds herein to inhibit Ras signaling in the cells. The cells (e.g., 800-1200 per well) are seeded in their respective culture medium in standard tissue culture -treated ultra-low attachment surface 96-well format plates (Coming Costar #3474). The day after plating, cells are treated with a dilution series (e.g., a 9 point 3-fold dilution series) of the compounds herein (e.g., approximately 125 pl, final volume per well). Cell viability can be monitored (e.g., approximately 5 days later) according to the manufacturer’s recommended instructions, where the CellTiter-Glo reagent is added (e.g., approximately 65 pL), vigorously mixed, covered, and placed on a plate shaker (e.g., approximately for 20 min) to ensure sufficient cell lysis prior to assessment of luminescent signal. The IC50 values are determined using the four-parameter fit. The resulting IC50 value is a measurement of the ability of the compounds herein to reduce cell growth of Ras-driven cells as representative tumor cells.

[0325]

[0256] Example 5: Inhibition of cell proliferation using SOS1 inhibitors in combination with amivantamab

[0326]

[0257] A variety of EGFR mutant cell lines are available commercially, including Ba / F3-EGFR_Ex20_ASV insertion cells, Ba / F3 EGFR L858R / T790M cells, PC9-EGFR Exl9 E746_A750 cells, andH1975-EGFR L858R / T790M cells. These exemplary cells can be maintained in a humidified incubator at 37 °C with 5% CO2 and grown in RPMI 1640 with 10% FBS (Gibco) and 50 IU mL'1penicillin / streptomycin (Gibco). For comparison of anti-growth activity, a CellTiter-Glo (CTG) luminescent based assay (Promega) is used. Cells (-300-1,200 per well) are seeded (using the same media) in standard tissue culture -treated 384-well format plates. The day after plating, cells are treated with a 9 point, 3 -fold dilution series of indicated compounds (40 pl, final volume per well) and growth inhibition is monitored -72 hours later (for BaF / 3 EGFR mutant lines) or 5 days later for other cell lines according to the manufacturer’s recommended instructions, where 20 pl, of CellTiter-Glo reagent is added, vigorously mixed, covered, and placed on a plate shaker for 20 min to ensure complete cell lysis prior to assessment of luminescent signal. Growth inhibition of cells treated with a SOS1 inhibitor of the present disclosure in combination with amivantamab are monitored as stated above.

[0327]

[0258] Example 6: Inhibition of tumor growth in EGFR exon 20 insertion murine model

[0328]

[0259] Mice are maintained under specific pathogen-free conditions, and food and water are provided ad libitum. For PDX models, BALB / c nude (NCr) mice are implanted with respective tumor fragments (2-3 mm in diameter) on the flank. Suitable exemplary PDX models include, but are not limited to, LU0858, LU0387 (ex20), LU3075 (ex20). To generate other TGI models, Ba / F3 EGFR mutant cell lines (1 x 106cells) are harvested on the day of use and injected in growth-factor-reduced Matrigel / PBS (50% final concentration in 100 pL). One flank is inoculated subcutaneously per mouse. Mice are monitored daily, weighed twice weekly, and caliper measurements begin when tumors become visible. Animals are randomly assigned to treatment groups as indicated in FIG. 1 by an algorithm that assigns animals to groups to achieve best case distributions of mean tumor size with lowest possible standard deviation. Tumor volume is calculated by measuring two perpendicular diameters using the following formula: (L x w2) / 2, in which L and w refer to the length and width of the tumor diameter, respectively. When tumors reach an average size of 100-200 mm3, mice are randomized and treated with vehicle or indicated compounds using the reported schedule. Results are expressed as mean and standard deviation of the mean. No apparent toxicity or body weight loss was observed. FIG. 1 shows that a SOS1 inhibitor of the present disclosure (Compound A) synergistically inhibits tumor growth in combination with amivantamab in EGFR exon 20 insertion lung cancer.

[0329] FIG. 3 shows that a SOS1 inhibitor of the present disclosure (Compound A) synergistically reduces tumor volume in combination with amivantamab in a PDX model (NSCLC-squamous, EGFR-Ex20 D772_N773insDNP) that is refractory to amivantamab.

[0330]

[0260] Example 7: Inhibition of tumor growth in MET-amplified murine model

[0331]

[0261] Mice are maintained under specific pathogen-free conditions, and food and water are provided ad libitum. For PDX models, BALB / c nude (NCr) mice are implanted with respective tumor fragments (2-3 mm in diameter) on the flank. To inoculate Ba / F3 EGFR mutant cell lines, 1 x 106cells are harvested on the day of use and injected in growth-factor-reduced Matrigel / PBS (50% final concentration in 100 pL). One flank is inoculated subcutaneously per mouse. Mice are monitored daily, weighed twice weekly, and caliper measurements begin when tumors become visible. Animals are randomly assigned to treatment groups as indicated in FIG. 2 by an algorithm that assigns animals to groups to achieve best case distributions of mean tumor size with lowest possible standard deviation. Tumor volume is calculated by measuring two perpendicular diameters using the following formula: (L x w2) / 2, in which L and w refer to the length and width of the tumor diameter, respectively. When tumors reach an average size of 100-200 mm3, mice are randomized and treated with vehicle or indicated compounds using the reported schedule. Results are expressed as mean and standard deviation of the mean. No apparent toxicity or body weight loss was observed. FIG. 2 shows that a SOS1 inhibitor of the present disclosure (Compound A) synergistically reduces tumor volume in combination with amivantamab in EGFR-mediated lung cancer, particularly MET amplified lung cancer.

[0332]

[0262] Example 8: Inhibition of tumor growth in EGFR L858R / T790M murine models

[0333]

[0263] Mice are maintained under specific pathogen-free conditions, and food and water are provided ad libitum. Female 6- to 8-week old athymic BALB / c nude (NCr) nu / nu mice are used to inoculate EGFR L858R / T790M cell lines. For example, H1975 cells (5 x 106) or Ba / F3 EGFR mutant cells (1 x 106) are harvested on the day of use and injected in growth-factor-reduced Matrigel / PBS (50% final concentration in 100 pL). One flank is inoculated subcutaneously per mouse. Mice are monitored daily, weighed twice weekly, and caliper measurements begin when tumors become visible. Animals are randomly assigned to treatment groups as by an algorithm that assigns animals to groups to achieve best case distributions of mean tumor size with lowest possible standard deviation. Tumor volume is calculated by measuring two perpendicular diameters using the following formula: (L x w2) 12, in which L and w refer to the length and width of the tumor diameter, respectively. When tumors reach an average size of 100- 200 mm3, mice are randomized and treated with either vehicle or a SOS1 inhibitor of the present disclosure (e.g., Compound A), amivantamab, or a combination thereof. Results are expressed as mean and standard deviation of the mean. FIG. 5 shows that a SOS1 inhibitor of the present disclosure (Compound A) synergistically reduces tumor volume in combination with amivantamab in mice bearing H820 xenograft tumors, a papillary adenocarcinoma model that is refractory to osimertinib and exhibits EGFR L858R / T790M mutations and MET amplification, with 8 of 8 animals in the combination group showing complete responses. As shown in FIG. 6, H820 xenograft tumors progress on amivantamab monotherapy, but when a S0S1 inhibitor of the present disclosure (Compound A) was added to the treatment regimen on day 22, tumors regressed, with 4 of 5 animals showing complete responses. FIG.

[0334] 7 shows that a SOS1 inhibitor of the present disclosure (Compound A) synergistically reduces tumor volume in combination with amivantamab in mice bearing Ba / F3 tumors transduced with mutant EGFR containing triple mutations in L858R, T790M, and C797S.

[0335]

[0264] Example 9: Inhibition of cell proliferation using SOS1 inhibitors in combination treatments

[0336]

[0265] A variety of EGFR mutant cell lines, including Ba / F3-EGFR_Ex20_ASV insertion cells, Ba / F3 EGFR L858R / T790M cells, PC9-EGFR Exl9 E746_A750 cells, and H1975-EGFR L858R / T790M cells, and METamp cell lines, including H820 cells, are available commercially. These exemplary cells can be maintained in a humidified incubator at 37 °C with 5% CO2 and grown in RPMI 1640 with 10% FBS (Gibco) and 50 IU ml / 1penicillin / streptomycin (Gibco). For comparison of anti-growth activity, a CellTiter-Glo (CTG) luminescent based assay (Promega) is used. Cells (-300-1,200 per well) are seeded (using the same media) in standard tissue culture- treated 384-well format plates. The day after plating, cells are treated with a 9 point, 3 -fold dilution series of either vehicle or (i) a SOS1 inhibitor of the present disclosure (e.g., Compound A) alone, (ii) amivantamab alone, or (iii) a combination of (i) and (ii) (40 id, final volume per well) and growth inhibition is monitored -72 hours later (for BaF / 3 EGFR mutant lines) or 5 days later for other cell lines according to the manufacturer’s recommended instructions, where 20 pL of CellTiter-Glo reagent is added, vigorously mixed, covered, and placed on a plate shaker for 20 min to ensure complete cell lysis prior to assessment of luminescent signal. Growth inhibition of cells treated with a SOS1 inhibitor of the present disclosure alone or in combination with amivantamab are monitored as stated above.

[0337]

[0266] Example 10: Inhibition of tumor growth in KRAS G12C murine model

[0338]

[0267] Mice are maintained under specific pathogen-free conditions, and food and water are provided ad libitum. For PDX models, BALB / c nude (NCr) mice are implanted with respective tumor fragments (2-3 mm in diameter) on the flank, such as CR9528 tumor fragments. Mice are monitored daily, weighed twice weekly, and caliper measurements begin when tumors become visible. Animals are randomly assigned to treatment groups as indicated in FIG. 4 by an algorithm that assigns animals to groups to achieve best case distributions of mean tumor size with lowest possible standard deviation. Tumor volume is calculated by measuring two perpendicular diameters using the following formula: (L x w2) / 2, in which L and w refer to the length and width of the tumor diameter, respectively. When tumors reach an average size of 100-200 mm3, mice are randomized and treated with vehicle or indicated compounds using the reported schedule. Results are expressed as mean and standard deviation of the mean. FIG. 4 shows that a SOS1 inhibitor of the present disclosure (Compound A) synergistically inhibits tumor growth in combination with amivantamab in KRAS G12C-mediated colorectal cancer.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of treating an EGFR-mediated cancer in a subject, comprising administering to the subject (a) a SOS1 inhibitor and (b) amivantamab, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b).

2. The method of claim 1, wherein the cancer is lung cancer.

3. The method of claim 2, wherein the lung cancer is a non-small cell lung cancer.

4. The method of any one of the preceding claims, wherein cancer cells of the subject comprise an EGFR mutation.

5. The method of claim 4, wherein the EGFR mutation is selected from an L858R mutation, an exon 19 deletion, and an exon 20 insertion.

6. The method of claim 4, wherein the EGFR mutation is an exon 20 insertion.

7. The method of any one of the preceding claims, wherein the subject exhibits relapse of the cancer.

8. The method of any one of the preceding claims, wherein the subject has previously been treated with chemotherapy.

9. The method of any one of the preceding claims, wherein the subject has previously been treated with platinum-based chemotherapy.

10. The method of any one of the preceding claims, wherein the subject has previously been treated with a tyrosine kinase inhibitor (TKI) against EGFR prior to administering (a) and (b).

11. The method of claim 10, wherein the subject has previously been treated with a non-exon 20 insertion EGFR TKI.

12. The method of claim 11, wherein the non-exon 20 insertion EGFR TKI is selected from gefitinib, erlotinib, afatinib, lazertinib, osimertinib, dacomitinib, neratinib, cetuximab, panitumumab, lapatinib, necitumumab, nazartinib, vandetanib, BLU-945, and zorifertinib.

13. The method of claim 10, wherein the subject has previously been treated with an EGFR exon 20 insertion TKI.

14. The method of claim 13, wherein the EGFR exon 20 insertion TKI is selected from poziotinib, mobocertinib, amivantamab, zipalertinib, sunvozertinib, BAY-2927088, BLU-451, and STX-721.

15. The method of any one of claims 10 to 14, wherein the subject exhibits resistance or intolerance to the TKI.

16. The method of claim 10, wherein the subject exhibits resistance or intolerance to osimertinib.

17. The method of claim 15 or 16, wherein resistance to the TKI is characterized by one or more changes selected from (1) progression of the cancer, (2) EGFR gene mutation, (3) loss of EGFR T790M mutation, (4) EGFR gene amplification, (5) MET amplification, (6) HER2 amplification, (7) RAS-MAPK pathway activation, (8) PI3K pathway activation, (9) cell-cycle gene alteration, (10) oncogenic fusion, (11) histologic transformation, and (12) phenotypic transformation.

18. A method of reducing proliferation of cancer cells comprising an epidermal growth factor receptor (EGFR) exon 20 insertion, the method comprising administering to the cells (a) a SO SI inhibitor and (b) amivantamab, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b).

19. The method of claim 18, wherein the cancer cells are non-small cell lung cancer cells.

20. The method of claim 18 or 19, wherein the administration of (a) and (b) synergistically reduces proliferation of the cancer cells with a synergistic value of at least 0.1 as ascertained by Bliss independence criterion.

21. The method of claim 20, wherein the synergistic value is ascertained by Bliss independence criterion in accordance with the formula:YAB.O - YAB.P wherein:Y AB.O is observed percent growth inhibition of the cancer cells by the application of (a) and (b) comprising (a) at dose A and (b) at dose B;Y AB.P is predicted percent growth inhibition of the cancer cells by the application of (a) and (b) comprising (a) at dose A and (b) at dose B, wherein YAB.P = YA + YB - Y \Yi;:YA is observed percent growth inhibition of the cancer cells by (a) alone at dose A;YB is observed percent growth inhibition of the cancer cells by (b) alone at dose B: and YAYB is the product of YA and YB.

22. The method of claim 20 or 21, wherein the synergistic value is at least 0.4.

23. The method of claim 20 or 21, wherein the synergistic value is at least 1.

24. The method of claim 20 or 21, wherein the synergistic value is at least 5.

25. A method of downregulating EGFR signaling output in a plurality of non-small cell lung cancer cells, comprising:(i) assessing EGFR mutation status in a biological sample comprising nucleic acid from the subject; and(ii) administering an effective dose of (a) a SOS1 inhibitor and an effective dose of (b) amivantamab if an EGFR exon 20 insertion is detected in the sample, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b).

26. The method of any one of claims 18 to 25, wherein the cancer cells have previously been treated with chemotherapy.

27. The method of any one of claims 18 to 25, wherein the cancer cells have previously been treated with platinum-based chemotherapy.

28. The method of any one of claims 18 to 27, wherein the cancer cells have previously been treated with a tyrosine kinase inhibitor (TKI) against EGFR other than amivantamab prior to administering (a).

29. The method of claim 28, wherein the cancer cells have previously been treated with a non-exon 20 insertion EGFR TKI.

30. The method of claim 29, wherein the non-exon 20 insertion EGFR TKI is selected from gefitinib, erlotinib, afatinib, lazertinib, osimertinib, dacomitinib, neratinib, cetuximab, panitumumab, lapatinib, necitumumab, nazartinib, vandetanib, BLU-945, and zorifertinib.

31. The method of claim 28, wherein the subject has previously been treated with an EGFR exon 20 insertion TKI.

32. The method of claim 31 , wherein the EGFR exon 20 insertion TKI is selected from poziotinib, mobocertinib, zipalertinib, sunvozertinib, BAY-2927088, BLU-451, and STX-721.

33. The method of any one of claims 18 to 32, wherein the cancer cells exhibit resistance or intolerance to the TKI.

34. The method of claim 33, wherein resistance to the TKI is characterized by one or more changes selected from (1) progression of the cancer, (2) EGFR gene mutation, (3) loss of EGFR T790M mutation, (4) EGFR gene amplification, (5) MET amplification, (6) HER2 amplification, (7) RAS-MAPK pathway activation, (8) PI3K pathway activation, (9) cell-cycle gene alteration, (10) oncogenic fusion, (11) histologic transformation, and (12) phenotypic transformation.

35. The method of any one of the preceding claims, further comprising administering (c) an additional agent or additional therapy.

36. The method of claim 35, wherein the additional agent is selected from an EGFR TKI other than amivantamab, a MET inhibitor, an immunomodulatory agent, an anti-nausea agent, an antiemetic, a pain reliever, and a chemotherapeutic agent.

37. The method of claim 35, wherein the additional agent is selected from an immunomodulatory agent, a cytokine blockade agent, and a checkpoint immune blockade agent.

38. The method of claim 35, wherein the additional agent is selected from an anti-PD-L l antibody, an anti- CTLA-4 antibody, an anti-PD-1 antibody, an anti-LAG3 antibody, an anti-TIM3 antibody, and combinations thereof.

39. The method of claim 35, wherein the additional therapy is selected from surgery, cell therapy, chemotherapy, and radiation.

40. The method of any one of the preceding claims, wherein the administration of (a) and (b) reduces incidence of one or more adverse event associated with amivantamab.

41. The method of claim 40, wherein the adverse event is selected from rash, pruritus, dry skin, fatigue, edema, pyrexia, paronychia, pneumonia, musculoskeletal pain, dyspnea, cough, nausea, stomatitis, constipation, vomiting, diarrhea, abdominal pain, hemorrhage, decreased appetite, peripheral neuropathy, dizziness, and headache.

42. The method of claim 40, wherein the adverse event is selected from diarrhea, rash, and nausea.

43. The method of any one of the preceding claims, wherein the administration of (a) and (b) exhibits a synergistic effect.

44. The method of claim 43, wherein the synergistic effect is characterized by a synergistic value of at least 0.05 as ascertained by Bliss independence criterion.

45. The method of any one of the preceding claims, wherein one or both of (a) and (b) are administered at a sub-therapeutic dose but achieve a therapeutic effect at least comparable to administering (a) or (b) alone at its therapeutically effective amount.

46. The method of any one of the preceding claims, wherein amivantamab is administered at a dose less than about 25% the standard monotherapy dose.

47. The method of any one of the preceding claims, wherein (a) and (b) are administered in the same formulation.The method of any one of the preceding claims, wherein (a) and (b) are administered in separate formulations.

49. The method of any one of claims 1 to 48, wherein the SOS1 inhibitor is a compound of Formula (1-1):or a pharmaceutically acceptable salt or solvate thereof, wherein:is selected from C5.7 carbocycle and 5- to 7-membered heterocycle, each of which is optionally substituted with one or more R11;is absent or selected from C3.8 carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more Rl la;L1is selected from a bond, Ci-6 alkylene, and Ci-6 haloalkylene:L2is selected from C5.25 alkylene, C5.25 alkenylene, C5.25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is optionally substituted with one or more Rl lb, wherein L2is covalently bound to one of W3, W4, W5, W6, or W7;W3is selected from N(R3b), N, C(R3), and C(O);W4is selected from N(R4b), N, C(R4), and C(O);W5is selected from N(R5b), N, and C(R5);W6is selected from C(R6) and C(O);W7is C(R7);R1is C1.3 alkyl optionally substituted with one or more Rllc;R8is selected from hydrogen, halogen, -CN, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10- membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), - N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), - N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), - CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein each Ci.6alkyl, C2.6alkenyl, C2.6alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20;R3, R4, R5, R6, and R7are each independently selected from a bond to L2, hydrogen, halogen, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), - C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20;R3b, R4b, and R5bare each independently selected from a bond to L2, hydrogen, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -C(O)OR12, - OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, - S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three R20;R11and Rllaare each independently selected at each occurrence from halogen, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), -CH2N(R12)S(O)2(R13), and - P(O)(R17)(R17a), wherein Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20;Rllbis independently selected at each occurrence from halogen, oxo, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), -CH2N(R12)S(O)2(R13), and - P(O)(R17)(R17a), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R11cis independently selected at each occurrence from halogen, -OR12, and -N(R12)(R13); R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R13is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R12and R13, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycle optionally substituted with one, two, or three R20; R14is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; R15is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20; R17and R17aare each independently selected at each occurrence from C1-6 alkyl and C3-6 cycloalkyl, wherein C1-6alkyl and C3-6cycloalkyl are optionally substituted with one, two or three R20; or R17and R17a, together with the phosphorous atom to which they are attached, form a 3- to 10-membered heterocycle; R20is independently selected at each occurrence from halogen, oxo, =NH, -CN, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C3-10 carbocycle, -CH2-(C3-10 carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, - S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, -CH2-(C3-10 carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, - N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; R21is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6 alkyl; R22is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6 alkyl; R23is independently selected at each occurrence from H and C1-6alkyl; R24is independently selected at each occurrence from H and C1-6alkyl; R25is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, C1-6 alkyl, C1-6haloalkyl, C1-6alkoxy, C3-10carbocycle, and 3- to 10-membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

50. The method of any one of claims 1 to 48, wherein the SOS1 inhibitor is selected from BI-3406,MRTX0902, BAY 293, RMC-5845, and BI-1701963.

51. A kit for use in reducing proliferation of cancer cells comprising an epidermal growth factor receptor(EGFR) exon 20 insertion, the kit comprising: (1) a composition comprising a SOS1 inhibitor of Formula (I-1); (2) a composition comprising amivantamab; and (3) instructions for using the composition(s) of (1) and (2).

52. The kit of claim 51, wherein the SOS1 inhibitor and the amivantamab are formulated in a same unit dosageform.

53. The kit of claim 51, wherein the SOS1 inhibitor and the amivantamab are formulated in different unitdosage forms.

54. A pharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (I-1), or a pharmaceuticallyacceptable salt or solvate thereof, (ii) amivantamab, and (iii) a pharmaceutically acceptable excipient.

55. A method of treating an EGFR-mediated cancer in a subject, comprising administering to the subject apharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (I-1), or a pharmaceutically acceptable salt or solvate thereof, (ii) amivantamab, and (iii) a pharmaceutically acceptable excipient.

56. The method of claim 1, 18, 25, or 55, wherein the subject is a naïve subject that has not been treated with aTKI against EGFR prior to administering (a) and (b).

Images